Open access

Alzheimer’s Disease and Diabetes

Written By

Brent D. Aulston, Gary L. Odero, Zaid Aboud and Gordon W. Glazner

Submitted: 18 September 2012 Published: 27 February 2013

DOI: 10.5772/54913

From the Edited Volume

Understanding Alzheimer's Disease

Edited by Inga Zerr

Chapter metrics overview

2,930 Chapter Downloads

View Full Metrics

1. Introduction

“I have lost myself”

- Auguste Deter, the first patient diagnosed with Alzheimer’s Disease, 1906

Identification of Alzheimer’s Disease Alois Alzheimer was a German neuropathologist and among the first to identify and describe the hallmarks of what is known today as Alzheimer’s disease (AD). In November of 1901, Dr. Alzheimer was presented with 51 year-old Auguste Deter who was suffering from mental incompetence, aphasia, disorientation, paranoia, and unprovoked bursts of anger. Deter’s emotional and mental devastation became evident when she confided to Dr. Alzheimer “I have lost myself.”

Symptoms similar to Deter’s had been observed in patients for years and were considered a natural part of aging. However, it was unusual for such a pointed disease state to occur in someone so young. Over the next four and half years, Deter became increasingly demented, until her death at the age of 55. Upon examination of Deter’s brain, Dr. Alzheimer found microscopic strands of protein which he described as “tangled bundles of fibrils” (neurofibrillary tangles) in addition to “miliary foci” (amyloid plaques). In 1906, at the 37th Conference of South-West German Psychiatrists in Tübingen, Alois Alzheimer presented Deter’s case as, “a peculiar disease of the cerebral cortex.”

To this day both the cause of and treatment for AD remain a mystery. AD is a multifaceted disease of great complexity, however, over 100 years of research has provided clues to its mechanisms. Of particular recent interest is the emerging realization that another rapidly growing disease, type 2 diabetes mellitus (T2DM), is linked to development of AD [1].

This chapter examines the current state of knowledge regarding the association of T2DM to vascular changes in the brain and the implications these changes have in AD development. Other factors that contribute to AD such as insulin resistance and accumulation of the neurotoxic peptide amyloid beta (Aβ) are also examined. It’s likely that no central cause of AD exists but rather, the disease represents a breakdown of several critical components involved in the general health and function of the brain.

Epidemiology of AD and T2DM AD is the most common form of dementia [2] and remains incurable. While the cause of AD remains unknown, several risk factors have been identified that may provide insight into the fundamentals of AD pathogenesis.

T2DM is a known risk factor for AD [1] suggesting that insulin signaling abnormalities play a central role in AD pathology. Moreover, AD brains show decreased insulin levels, decreased activity of insulin receptors and signs of compensatory mechanisms such as increased insulin receptor density [3] indicating AD as “type 3 diabetes” [4, 5].

Loss of insulin signaling in diabetes can occur by either type 1 or type 2 processes. Type 1 diabetes mellitus (T1DM) is characterized as an autoimmune disease that results in the destruction of insulin producing β cells found in the pancreas. In contrast, T2DM is a state of insulin resistance in which insulin levels are normal or elevated but tissues are unresponsive to its effects. While both T1DM and T2DM can lead to cognitive deficits, T2DM poses a greater risk for AD development [6, 7] and as a result the parallels between T2DM and AD are studied more vigorously than T1DM associations. Therefore, the majority of information presented here pertains to type 2 diabetic pathologies.

In addition to insulin resistance, T2DM is associated with the development of vascular dysfunction in the brain [8, 9]. T2DM is a risk factor for microvascular complications as well as macrovascular defects [10] such as stroke [11]. Vascular abnormalities are strongly associated with AD [12-16] implying further involvement of T2DM in disease onset.

Advertisement

2. Type 2 diabetes, vascular changes and Alzheimer’s disease

Insulin signaling in the vasculature Activation of the insulin receptor (IR) leads to phosphorylation of insulin receptor substrate (IRS) which serve as docking proteins for phosphatidylinositol 3-kinase (PI3K). PI3K generates phosphatidyl-3,4,5-triphosphate (PIP3) which then phosphorylates 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Finally, PDK-1 phosphorylates Akt and stimulates endothelial nitric oxide synthase (eNOS) resulting in the production of nitric oxide (NO) and vascular relaxation [17, 18]. Interestingly, insulin receptor activation can also mediate vasoconstriction. Activation of IR can also lead to phosphorylation of Shc which then binds Grb-2 resulting in activation of Sos. This complex then activates Ras leading to phosphorylation Raf which results in activation of MAPK. Activation of MAPK stimulates release of endothelin-1 (ET-1), a vasoconstrictor [19-21]. By mediating vascular properties, insulin signaling plays a significant role in glucose and oxygen availability to the brain. Conversely, dysfunction in insulin signaling, as observed in T2DM, has profound detrimental effects on hemodynamics and, thus, maintenance of normative brain function.

Vascular complications associated with type 2 diabetes It is estimated that approximately 200 million people worldwide have diabetes and by 2025 the number is expected to increase to 333 million [22]. Epidemiological studies have indicated that patients with T2DM have a greater incidence of cardiovascular disease, cerebrovascular disease (CVD), hypertension and renal disease relative to the general population [8, 9]. In addition, a large number of population-based studies have identified diabetes as a risk factor for dementia [23-25], primarily as a result of CVD [26, 27]. At only 3% of body weight, the brain uses ~20% of the body’s oxygen and ~25% of the body’s blood glucose [28, 29], demonstrating that it is by far the most metabolically active organ. This oxygen and glucose consumption is constantly required, since brain neurons are obligate aerobic cells and have no other source of energy. The majority of this energy is used to maintain cellular ionic homeostasis, and thus when cerebral blood flow (CBF) ceases, brain function ends within seconds and damage to neurons occurs within minutes [30].

The vascular complications associated with diabetes can be divided into two classes based on the vascular etiology of their pathology: macrovascular (hypertension, coronary artery disease, atherosclerosis, stroke) and microvascular (neuropathy, retinopathy, nephropathy). Macrovascular complications are those that affect the larger (non-capillary) blood vessels. Statistics show that diabetes increases the risk of stroke and atherosclerosis [31]. Atherosclerosis accounts for 70% of morbidity associated with T2DM [32], while other studies have shown an association between the degree of hyperglycemia and increased risk of myocardial infarction and stroke [33-36]. While macrovascular complications themselves represent important pathological consequences of T2DM, they have also been shown to provide the etiological link between T2DM and the development of Alzheimer’s disease.

Link between type 2 diabetes and Alzheimer’s disease AD is an age-related disorder characterized by progressive cognitive decline and dementia. An estimated 5.3 million people in the United States are currently affected and represents the sixth-leading cause of death. Significant evidence has been provided that links T2DM to AD. For example, a comprehensive meta-analysis showed that the aggregate relative risk of AD for people with diabetes was 1.5 (95%-CI 1.2 to 1.8) [37]. Studies have shown that T2DM, impaired fasting glucose and increased islet amyloid deposition are more common in patients with Alzheimer’s disease than in control subjects [38, 39]. Unsurprisingly, insulin signaling provides an important mechanistic link between T2DM and AD.

Ischemic CVD caused by T2DM is positively associated with AD through shared pathological mechanisms such as hyperinsulinemia, impaired insulin signaling, oxidative stress, inflammatory mechanisms and advanced glycation end-products (AGEs) [40]. Defective insulin signaling is associated with decreased cognitive ability and development of dementa, including AD [41], rendering signaling neurons more vulnerable to metabolic stress and accelerating neuronal dysfunction [42]. In vitro insulin-stimulated Akt phosphorylation is decreased in hyperinsulinemic conditions in cortical neurons [43]. Finally, all forms of amyloid beta (Aβ) (monomers, oligomers and Aβ-derived diffusible ligands (ADDLs)) can inhibit insulin signaling by directly binding to the insulin receptor and inhibit insulin signaling [44].

Mechanisms of macrovascular complications of diabetes A central pathological mechanism in diabetic-related macrovascular disease is atherosclerosis, which leads to the hardening of arterial walls throughout the body resulting in impaired blood flow. Although the mechanism for the susceptibility of diabetic patients to ischemic heart disease remains unclear, accumulating lines of evidence implicate hyperglycemia, hyperlipidemia and inflammation as playing key roles in the development of this disorder [45]. This link between obesity and both T2DM and atherosclerosis implicates elevated amounts of glucose oxidized LDL and free fatty acids (FFAs) in disease pathogenesis, potentially as triggers for the production of pro-inflammatory cytokines by macrophages [32].

In the insulin resistant state, there is a specific impairment in the vasodilatory PI3K pathway, whereas the Ras/MAPK-dependent pathway is unaffected [46, 47]. This results in decreased production of NO and an increased secretion of ET-1 in humans [48] leading to increased vasoconstriction. The decrease in NO production is significant in that NO protects blood vessels from endogenous injury by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell proliferation and migration [49, 50]. Decreased production of NO allows for increased expression of proinflammatory transcription factor NF-κB, and subsequent expression of leukocyte adhesion molecules and production of chemokines and cytokines [51]. Activation of these proteins promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, initiating the morphological changes associated with the onset of atherosclerosis [52, 53].

Figure 1.

Pathways leading to macrovascular complications of type 2 diabetes mellitus (T2DM). In non-diabetic individuals (left), activation of the insulin receptor can result in activation of both vasodilatation and vasoconstriction. Under normative conditions, there is a balance of both processes to regulate the immediate metabolic requirements of various tissues. In type 2 diabetic patients (right), factors such as an increase in free fatty acids and hyperglycemia have been shown to specifically inhibit the Akt pathway while the MAPK pathway remains unaffected. This leads to an imbalance in homeostatic regulation of vascular function and hemodynamics (1). The resultant decrease in nutrient availability to affected tissues results in an increase in oxidative stress and ROS production and an increased inflammatory response (2). Released pro-inflammatory cytokines and macrophage recruitment instigates the onset of atherosclerosis, ultimately leading to macrovascular complications (3).

High levels of FFAs are found in insulin-resistant individuals. FFAs generated by increased activity of hormone-sensitive lipase that contribute to and result in insulin resistance [54-56]. In vitro vascular endothelial cell culture treated with FFA resulted in decreased insulin-stimulated eNOS activity and NO production [57]. It is believed that FFA increases cellular levels of diacylglycerols, ceramide, and long-chain fatty acyl coenzyme A (CoA), all of which have been shown to activate protein kinase C (PKCβ1). Activation of PKCβ1 results in increased phosphorylation of IRS-1 that leads to reduced Akt and eNOS resulting in decreased vasodilatory capacity [58, 59]. Increase in FFAs result in an increase in reactive oxygen species (ROS) from NADPH and the mitochondrial electron transport chain [60]. The increase in ROS results in increased PKC which activates the hexosamine biosynthetic pathway leading to increased AGEs and subsequent decrease in endothelial-derived NO [60]. Hyperglycemia has been found to decrease activation of Akt and eNOS via O-GlcNAC of eNOS at the Akt phosphorylation sites [61, 62]. Hyperglycemia increases activation of PKCα, PKCβ, PKCδ resulting in decreased eNOS and concomitant increase in endothelial ET-1 [60]. T2DM is associated with vascular dysfunction as a result of increased atherosclerosis and decreased cerebral blood flow. The combination of both processes is decreased glucose and oxygen supply to vital organs such as the brain. The biochemical events leading to the macrovascular impairment has particular significance to brain health as the risk of stroke is a major complication of T2DM.

Type 2 diabetes and cardiovascular disease T2DM has been shown to be associated with an increased risk of coronary heart disease and stroke [63-66]. Insulin resistance, the mechanism underlying T2DM, has also been linked to a higher incidence and recurrence of stroke [67]. Two key pathological mediators of stroke observed in T2DM are intracranial stenosis [68] and carotid atherosclerosis [69]. Insulin resistance has been associated with elevated expression of the fibrinolytic inhibitor plasminogen activator inhibitor 1 [70] resulting in decreased fibrinoyltic capacity and concurrent increased thrombosis due, in part, to an increase in platelet activation [71]. Insulin resistance has also been shown to induce endothelial dysfunction and inflammation [71], adversely affecting vascular function and initiating atherosclerosis, respectively. Collectively, these data implicate insulin resistance to the impairment of normative cerebrovascular function resulting in the activation of pathways that encourage the onset of stroke. Stroke could, in turn, exacerbate and/or initiate the onset of another disorder such as AD.

Pre-existing CVD has been identified as a significant risk factor for AD. The vascular hypothesis of AD posits that vascular dysfunction, such as stroke, is a pre-requisite for the development of this disorder. It has been reported that the risk of AD is three times greater after the occurrence of stroke [72]. Stroke may result in neurodegeneration [73, 74], resulting in the rapid cognitive decline observed in AD patients [75]. It has even been proposed that stroke may be the underlying cause of 50% of AD cases [74]. Conversely, individuals presenting with severe cognitive impairments, and possibly AD, may be at a greater risk for the development of stroke or CVD [76, 77].

The amyloid hypothesis of AD was long held as the prevailing theory explaining the etiology of AD. However, emerging evidence compiled from the last 20 years has suggested that the pathology associated with AD is vascular in origin. The vascular hypothesis of AD states that pre-existing cardiovascular dysfunction such as stroke, hypertension and atherosclerosis results in chronic cerebral hypoperfusion that could encourage the onset of AD. Several lines of evidence have been provided in support of this hypothesis. For example, it has been shown that cerebrovascular dysfunction precedes cognitive decline and the onset of neurodegenerative changes in AD and AD animal models [12, 13]. In rhesus monkeys, dystrophic axons labeled with amyloidogenic enzyme, BACE1, were found in close proximity or in direct contact with cortical blood vessels [78], asserting a tight association with AD pathology and vascular dysfunction. Clinical and epidemiological evidence provides further support of the vascular hypothesis.

AD patients show a greater degree of vascular narrowing of carotid arteries [65] and cerebral arteries of the Circle of Willis [79, 80]. In addition, large artery CVD was positively correlated to the frequency of neuritic plaques [81]. Several vascular risk factors such stroke (silent infarcts, transient ischemic attacks), atherosclerosis, hypertension, heart disease (coronary artery disease, atrial fibrillation) and diabetes mellitus have been associated with an increased risk AD-type dementia [82]. Between 60 to 90% of AD patients exhibit various cerebrovascular pathologies including White matter lesions, cerebral amyloid angiopathy (CAA), microinfarcts, small infarcts, hemorrhages and microvascular degeneration [12-16]. It believed that cardiovascular dysfunctions act as a nidus for accelerated Aβ deposition resulting in the onset of AD [83].

Aberrant blood brain barrier (BBB) function exposes neurons to neurotoxic substances. Chronic cerebral hypoperfusion is believed to render the brain more vulnerable to various insults, resulting in AD and associated cognitive loss [84]. Clinical observations in AD patients have revealed extensive degeneration of endothelium [85] and features indicative of BBB breakdown [86]. At the cellular level, AD is known to cause abnormal structural changes to arterioles and capillaries, swelling and increased number of pinocytotic vesciles in endothelial cells, decreased mitochondrial content, increased deposition of proteins of the basement membrane, reduced microvascular density and occasional swelling of astrocyte endfeet [87-92]. Aβ trafficking across the BBB deposition is also dependent on mechanisms of influx and efflux. Increased expression of receptor for advanced glycation endproducts (RAGE) may be responsible for Aβ influx from the blood to the brain has been reported in addition to a decrease in LRP1 receptors that are responsible for clearing Aβ from the brain to the blood [12, 93].

A functional consequence associated with BBB dysfunction is the resultant impairment in cerebral hemodynamics. AD impairs autoregulation, the mechanism that is responsible for the stabilization of blood flow to the brain in response to changes in cerebral perfusion pressure [94]. In an APP x PS1 mouse model neurovascular coupling, the process in which activation of a brain region evokes a local increase in blood flow, was impaired [95]. Finally, AD has shown to adversely affect vasomotor/vascular reactivity, the process that mediates vasodilatory or vasoconstrictor responses of cerebral blood vessels to hypercapnic or hypocapnic stimuli (ie. global or regional brain blood flow response to systemic changes in arterial CO2) [96-98]. Cumulatively, the impairment of these processes adversely affects cerebral blood regulation that, in turn, would negatively affect nutrient availability to neurons. This would result in cerebral hypoperfusion, a process that is widely believed to initiate the onset of AD pathology.

There are a number of known direct links between biochemical pathways central to AD and hypoxia/ischemia. A rat model for vascular cognitive impairment has been developed referred to as the two-vessel occlusion model of cerebral ischemia. Studies found decreased cerebral blood flow up to 4 weeks, cognitive deficits, APP proteolysis to form Aβ-sized fragments [99-101]. Other studies have observed an overexpression of Aβ persisting for up to 3 months after surgery [102] and cognitive impairment [103], strongly suggesting that decreased CBF is a key mediator in the pathophysiology of AD. Several studies have been able to identify some of the molecular mechanisms as to how hypoxia/ischemia exerts its effects on AD-related genes.

APP expression increases following chronic cerebral hypoperfusion and ischemia [104, 105], and a greater proportion of APP is proteolytically cleaved by increased activity of amyloidogenic enzyme, BACE1, which is concurrently increased in AD following ischemic events [106]. Hypoxia inducible factor-1α (HIF-1α) plays an essential role in cellular and systemic responses to low oxygen and has been found to increase BACE1 mRNA expression [107]. Furthermore, BACE1 stabilization is enhanced in AD in addition to a decrease in its trafficking [108, 109]. Increased BACE results in greater γ-secretase-mediated production of Aβ [110]. In an APP overexpressing mouse model, chronic cerebral hypoperfusion as the result of cerebral amyloid angiopathy (pathological deposition of Aβ1-40 in brain blood vessels) was followed by an increased rate of leptomeningeal Aβ precipitating the risk of microinfarcts [111]. Hypoxia/ischemia not only causes increased amyloidogenic cleavage of APP and greater Aβ production, but also impairs Aβ degradation and trafficking [12, 112].

Decreased Aβ-degrading enzymes in response to hypoxic conditions increase the likelihood of developing pathological levels of Aβ in the brain [113-115]. Aβ serves not only as the end result of a pathological cascade, but Aβ itself has been found to contribute to dysfunction in components of the neurovascular unit. In endothelial cells Aβ was observed to decrease endothelial cell proliferation and accelerate senescence of endothelial cells in vivo and in vitro, inhibit VEGF-induced activation of Akt and eNOS in endothelial cells [116, 117]. Aβ has been found to decrease eNOS (via PKC-dependent pathway) resulting in decreased vascular tonus and decreased substance P-induced vasodilation of the basilar artery[118, 119]. In vascular smooth muscle cells (VSMCs), Aβ affects cellular morphological changes [120] and increases expression of transcription factors, serum response factor and myocardin, resulting in decreased Aβ clearance by downregulating LRP expression [12]. Finally, Aβ has been shown to cause retraction and swelling of astrocyte endfeet in an AD mouse model with CAA [121] as well as increase cholinergic denervation of cortical microvessels which, taken together, results in impaired functional hyperemia [122].

Type 2 diabetes and vascular dementia A significant number of population-based studies have indicated an increased risk for the development of dementia attributed to T2DM [23-25]. Due to the importance of insulin in the regulation of several cardiovascular functions, it is unsurprising that insulin resistance plays a role in the cerebrovascular mechanisms of T2DM-induced dementia. The presence of brain infarcts in demented diabetics who did not have AD has been reported 123. Interestingly, the association between T2DM and the development of AD and VaD has been found to be independent of hypertension and hypercholesterolemia [23] indicating that is CVD alone is not sufficient to initiate dementia. Non-cerebrovascular mechanisms such as peripheral hyperinsulinemia and generation of advanced glycation end-products also play in the etiology of T2DM-related dementia [124]. Studies have shown that the increased risk of developing vascular dementia was greater than developing AD in type 2 diabetics [7, 125, 126], indicating that although symptomatically similar and frequently confused [127], their etiologies are distinct.

Vascular dementia versus Alzheimer’s dementia The leading cause of dementia is Alzheimer’s disease accounting for 70-90% of all cases [127], while vascular dementia (VaD) accounts for the majority of the remaining incidents of dementia [128]. They share common risk factors including hypertension, diabetes mellitus, and hyperlipidemia. [129], highlighting the tight association between these two forms of dementia. In fact, it is now widely believed that AD and VaD are frequently present in the same brain. So-called “mixed dementia” has been observed in elderly people with cardiovascular risk factors in addition to slow progressive cognitive decline [130].

Differing clinical manifestations separate VaD from AD dementia. For example, VaD progression appears more varied than AD in relation to symptoms, its rate of progression and the disease outcome [131]. Increased damage to the ganglia-thalamo-cortical circuits specific to VaD results in problems with attention and the planning and speed of mental processing whereas the primary impairments characteristic of AD are memory and language-related [132]. It has been suggested that differences in the clinical observations in AD and VaD patients may be due to the type, severity and location of vascular damage [133-135]. Furthermore, perturbations in vascular hemodynamics have been observed in VaD and AD [136, 137], however, AD patients had comparatively less impairment in cerebral perfusion than those with VaD [138] suggesting that hemodynamic disturbances may underlie different types of dementia [138]. While the precise mechanism that vascular risk factors initiate cognitive decline remains elusive [139], T2DM have been identified as an important contributing factor to the development of VaD.

Associations between vascular dementia and Alzheimer’s dementia While regarded as two separate conditions, AD and VaD share common cerebrovascular pathologies such as CAA, endothelial cell and vascular smooth muscle cell degeneration, macro- and microinfarcts, hemorrhage and white matter changes [140-142]. These shared pathologies have been shown epidemiologically with almost 35% of AD patients showing evidence of cerebral infarction at autopsy [143, 144], and, conversely, VaD patients display AD-like pathology in the absence of pre-existing AD [145]. It has been postulated that CVD, thought to be the etiology of both disorders, not only result in dementia but also increase the likelihood of individuals with AD-related lesions for developing dementia [146, 147].

Advertisement

3. Insulin signaling in the brain

Insulin/IGF-1 pathway activation. The brain is a major metabolic organ that accounts for ~25% of the body’s total glucose use [28, 29]. While glucose uptake in peripheral tissues requires insulin, in the brain this is considered to be an insulin-independent process. Insulin, however, along with Insulin-like Growth Factor-1 (IGF-1), are required for proper brain function as they provide critical neurotrophic support for neurons. IGF-1 and insulin share similar amino acid sequences/ tertiary structures [148] and are known to bind to and activate one anothers’ receptors [149]. Both insulin and IGF-1 receptors are tyrosine kinases [150-152] that, when activated, phosphorylate substrate proteins such as IRS. IRS phosphorylation leads to downstream activation of PI3K and Akt, a serine/threonine kinase and key mediator of insulin/IFG-1’s neurotrophic effects. Neuronal processes known to be, at least in part, under the control of insulin/IGF-1 include regulation of apoptotic proteins, transcription of both survival and pro-death genes, neurite outgrowth, and activity of metabolic proteins.

The source of brain insulin remains controversial. While preproinsulin mRNA has been reported in the neurons [153-155], very little insulin is synthesized in the brain [156]. Additionally, glial cells have been found not to be involved in insulin production [157], therefore, it is recognized that the majority of insulin in the brain is produced by pancreatic β cells [158-161]. In contrast, IGF-1 is produced locally in the brain and does not depend on growth hormone influence as is the case of liver and other tissues [148].

Neuronal insulin receptors are different than those found in the periphery [162]. Insulin receptors are present in one of two isoforms; the IR-A isoform that lacks exon 11 that the other isoform, IR-B, expresses [163, 164]. A major functional difference between the two isoforms is that IR-A has a higher affinity for the neurotrophic factor Insulin-like Growth Factor – 2 (IGF-II) [165] and a slightly higher affinity for insulin [166] and has also been shown to associate/dissociate with insulin quicker than IR-B [149]. Brain specific insulin receptors are mainly the IR-A isoform and as result of differential glycosylation have a lower molecular weight than their peripheral counterparts [162].

Structurally, the insulin receptor is a homodimer composed 2α chains and 2β chains held together with disulphide bonds [167-169]. Insulin receptor binding of insulin/IGF-1 results in a conformational change that activates the catalytic tyrosine kinase activity of the β subunits [170]. This activation of the insulin receptor results in autophosphorylation at multiple tyrosine residues [171, 172] including tyrosine 960 in the juxtamembrane region of the β subunit [173, 174]. Phosphorylation at this site is a vital component of the insulin signaling cascade because it provides a binding motif for the phospho-tyrosine binding (PTB) domain of IRS [173, 174]. Once docked to the insulin receptor, IRS is phosphorylated on tyrosine residues [170].

Tyrosine phosphorylation of IRS proteins creates binding sites for Src homology 2 (SH2) domain containing proteins such as PI3K [175]. PI3K catalyzes the production of 3’phosphoinositide secondary messengers which are critical to the insulin signaling cascade. PI3K is composed of a catalytic p110 subunit and a regulatory p85 subunit that contains SH2 domains that interact with activated IRS [176]. Formation of the IRS/PI3K complex increases the catalytic activity of the p110 subunit [177].

3’phosphoinositides produced by PI3K are important signal conductors that bind to PH (pleckstrin homology) domains on proteins such as IRS [177] and Akt [178]. This interaction is needed to bring IRS and AKT proteins towards the inner layer of the plasma membrane near the juxtamembrane region of the insulin receptor [179] and in close proximity to activating kinases, respectively [180-185]. Furthermore, binding of 3’phosphoinositides is required for Akt to be competent for phosphorylation [184, 186-188].

Akt has two phosphorylation sites, Thr 308 and Ser 473, capable of inducing catalytic activity [189]. PDK1, which also depends on 3’phosphoinosites for its function, phosphorylates Akt at Thr 308 [189, 190].While overexpression of PDK1 has been shown to activate Akt [186], optimal activation of Akt requires additional phosphorylation at Ser 473 by mTORC2 [191] which stabilizes the conformation state of Akt [192].

Akt mediates the neurotrophic effects of insulin/IGF-1, in part, by inhibiting pro-apoptotic machinery [193] and concomitantly activating anti-apoptotic proteins [194-198]. Akt’s role in neurotrophic support also involves the regulation of survival transcription factors such as NF-κB [199] and CREB [198] as well as those involved in pro-death gene expression such as the FoxO family [200-202]. Moreover, Akt is involved in production of the neurotrophin BDNF [198], activation of proteins involved in neurite outgrowth (for review see: [203]) and regulation of the metabolic protein GSK-3β [204].

Akt and Bcl-2 family members The Bcl-2 family is a structurally related group of proteins that regulate cell death through effects on the mitochondria [205] (for review see [206, 207]). Bcl-2 members include the pro-apoptotic proteins BID, BIM, PUMA, BAD, NOXA, BAX, and BAK [205] along with anti-apoptotic mediators such as Bcl-2 and Bcl-xL [205]. Because Bcl-2 proteins possess the ability to form heterodimers with one another [208-210], their regulation of apoptosis can be described as a balancing act in which an increase of anti-apoptotic members leads to survival while increased pro-death proteins result in apoptosis.

Mitochondrial stress incurred by ROS can lead to elevated Ca2+ levels in the mitochondrial matrix [211, 212] resulting in increased mitochondrial membrane permeability and release of pro-apoptotic factors such as Cytochrome c, and AIF (apoptosis inducing factor) [213]. Bcl-xL is an anti-apoptotic Bcl-2 family member that prevents Ca2+ induced mitochondrial permeability [214]. In the absence of insulin/IGF-1 stimulation, the survival effects of Bcl-xL are blocked as Bcl-xL is complexed with the pro-death Bcl-2 family member Bad [215-217]. Akt liberates Bcl-xL by phosphorylating Bad [195-197, 218] allowing for mitochondrial stabilization.

Mitochondrial permeability marks a critical event in the cell death cascade. Akt promotes cell survival prior to Cytochrome c release through Bcl-xL activity but has also been found to act post apoptotic factor release. When Cytochrome c is released from the mitochondria, it will associate with Apaf-1, dATP and Caspase-9 forming a structure known as the apoptosome (For review see [219]). Formation of the apoptosome activates the proteolytic activity of caspase-9 which cleaves and activates other caspases critical to the apoptotic process [220, 221]. Akt blocks apoptosome formation by phosphorylating Caspase 9 [193].

Bcl-2 is another anti-apoptotic protein under the control of Akt [222]. Bcl-2’s role in cell survival is similar to that of Bcl-xL in that in maintains mitochondrial membrane integrity [223]. Mitochondrial permeability has been linked to an oxidized shift in the mitochondria [224] while Bcl-2 has been shown to promote a more reduced state [225]. Up-regulation of Bcl-2 may lead to higher cell reductive capacity [224] which is supported by the observation that Bcl-2 overexpressing cells show increased amounts of NADPH and are resistant to ROS generation [226].

The Bcl-2 promoter contains a cAMP response element site (CRE) that can enhance Bcl-2 expression by binding the transcription factor CREB. Akt is known to phosphorylate CREB which results in increased CREB binding to CBP and increased transcriptional activity [198]. Therefore, the ability of Akt to promote cell survival is mediated, in part, by influence over gene expression such as the up-regulation of Bcl-2 [227-230] and through direct protein interactions such as Bad phosphorylation resulting in Bcl-xL liberation [194-197].

Akt and transcription factor regulation Also under CREB transcriptional control is the neurotrophic factor BDNF [231, 232] which is essential for neuronal development, differentiation, synaptic plasticity, neuroprotection and restoration against a broad range of cellular insults [233]. BDNF has been a focus of AD research for its ability to stimulate non-amyloidogenic APP processing pathways [234, 235] in addition to protecting neuronal cultures against the cytotoxic effects of Aβ [236]. This indicates that decreased insulin signaling resulting in reduced BDNF production may be a contributing factor in AD development. In accordance, AD patients have decreased serum BDNF concentrations compared to healthy, elderly subjects [237-241] while reduced BDNF levels were associated with decreased cognitive performance in healthy individuals [242].

The transcription factor NF-κB is also under Akt control [199]. Like CREB, NF-κB plays critical roles in neuron survival [201, 243, 244] and is also involved in neurite outgrowth, myelin formation and axonal regeneration [245]. Genes for antioxidant proteins such as MnSOD [246] and Cu/ZnSOD [247] and anti-apoptotic proteins Bcl-2 and Bcl-xL are targets of NF-κB [248].

In its inactive form, NF-κB is bound to IκB proteins that sequester it to the cytosol (for review see [249, 250]). NF-κB is activated when IκB proteins are phosphorylated by IκB Kinase (IKK) complexes and targeted for degradation which allows NF-κB to translocate to the nucleus where it binds to regulatory DNA sequences [251]. The IKK complex consists of catalytic IKKα and IKKβ subunits and a regulatory IKKγ subunit [251]. Akt facilitates NF-κB activation by phosphorylating IKKα at a critical regulatory site that promotes IKK activation [252] and subsequent IκB degradation.

Akt influence is not limited to only survival transcription factors but extends to pro-death modulators as well [253, 254].The forkhead box class O (FoxO) family of transcription factors contribute to apoptosis through the induction of pro-death genes such as Fas L [201, 255, 256] and the Bcl-2 member BIM-1 [257]. Fas L facilitates apoptosis by activation of caspases [258] while BIM-1 activates the pro-apoptotic Bcl-2 family memeber BAX [259]. In the absence of Akt, FoxO transcription factors are transcriptionally active in the nucleus [200-202]. Akt phosphorylates FoxO family members at a conserved c-terminal sequence [253] which leads to nuclear exclusion and inhibition of transcriptional activity.

p53,another pro-death transcription factor known to be inactivated by Akt, [260] induces the expression of the pro-apoptotic Bcl-2 family member BAX. BAX proteins form oligomers that insert into the outer mitochondrial membrane which provide a passageway for Cytochrome c and other pro-apoptotic proteins to escape through [261]. Increased p53 activity leading to BAX expression has been linked to neuronal deprivation of neurotrophic factors [262].

Akt and neurite outgrowth Akt effects extend beyond apoptosis regulation as Akt also contributes to neurite outgrowth (for review see [203]). In hippocampal neurons Akt enhances characteristics such as dendritic length/complexity, caliber, and branching [263-267] with similar effects, excluding dendritic length, observed in dorsal root ganglia neurons [268-271]. Akt substrates implicated in neurite outgrowth include GSK-3β [272, 273], CREB [198], mTOR [274], peripherin [275], and β-catenin [276]. Akt may also work in conjunction with other pathways involved in neurite outgrowth. For example, Akt has been found to be complexed with Hsp-27 (heat shock protein) in spinal motor neurons following nerve injury [277] as well as in areas of regeneration following sciatic nerve axotomy [278].

Akt and GSK-3β Activity of the metabolic protein GSK-3β is also influenced by Akt. GSK-3β was originally identified for decreasing glycogen production through inhibition of glycogen synthase [272, 279-281]. However, GSK-3β is also involved in protein synthesis, cell proliferation/differentiation, microtubule dynamics, cell motility and apoptosis. Of particular interest, GSK-3β has also been shown to phosphorylate cytoskeletal associated tau proteins [282] which, in a diseased state, result in protein aggregates known as neurofibrillary tangles [283]. Neurofibrillary tangles have been linked to increased oxidative stress, mitochondrial dysfunction and apoptosis [284, 285] and are the most significant structural correlates of dementia in AD [286, 287]. IGF-1 protects neurons from ischemic damage by reducing GSK-3β activity [288] which implies a critical role of Akt in GSK- 3β regulation. Indeed, Akt has been shown to inhibit GSK-3β [204] thus demonstrating a direct role of insulin/IGF-1 signaling in the prevention of AD pathology.

Figure 2.

Insulin receptor binding of insulin triggers a complex signaling cascade (in blue) leading to activation of the serine/threonine kinase Akt. Upon binding of insulin, insulin receptors are autophophorylated and subsequently bind IRS proteins. IRS proteins are then phsophorylated by activated insulin receptors and complex with PI3K resulting in PI3K activation. Activated PI3K produces phospholipid secondary messengers by catalyzing the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 messengers activate PDK1 which phosphorylates Akt at Threonine 308. Akt is further activated by phosphorylation at Ser 473 by mammalian target of rapamyicin 2 (mTORC2). Targets of activated Akt include pro-apoptotic mediators (in red) as well as pro-survival machinery (in green). Loss of insulin signaling (at sites labeled with numbers 1-6 in purple) allows FoxO and p53 transcription factors to remain active and (1) transcribe genes for pro-apoptotic proteins such as BIM, BAX and FasL. Akt inhibits the activity of GSK-3β that, when active, (2) causes increased amyloidogenic processing and hyperphosphorylation of tau. Other pro-apoptotic proteins inhibited by Akt include (3) caspase-9, which forms an apoptotic structure known as the apoptosome, and (6) Bad, which blocks activity of the ant-apoptotic protein Bcl-xL. Pro-survival modulators regulated by Akt include CREB and NF-κB. Reduction of CREB transcriptional activity as a result of a loss of insulin signaling leads to (4) decreased BDNF and Bcl-2 expression while inhibition of NF-κB leads to (5) reduced expression of anti-oxidants such as MnSOD and CuSOD as well as anti-apoptotic Bcl-2 family members.

Loss of insulin signaling While not a cause of death on its own, loss of insulin signaling in the brain leaves neurons vulnerable to a myriad of insults. Insulin signaling is known to protect against oxidative stress, mitochondrial collapse, over-activity of GSK-3β leading to hyperphosphorylation of tau, activation of death promoting transcription factors and formation of apoptotic structures. Insulin also results in increased BDNF neurotrophic support as well as increased neurite outgrowth.

The mitochondrial permeability transition mediates apoptosis through the release of pro apoptotic factors. Insulin signaling maintains mitochondrial membrane integrity by increasing levels and activity of anti-apoptotic Bcl-2 family members [194-197, 227-230]. In the absence of insulin signaling, the balance of Bcl-2 proteins tips in favor of pro-apoptotic members resulting in cell death. Post mitochondrial collapse, normal insulin signaling can still prevent apoptosis by blocking formation of apoptotic complexes [193, 229] while a state of insulin resistance allows this process to continue unimpeded.

Even under normal circumstances, ROS are produced in respiratory chain reactions in the mitochondria [289]. However, if not properly managed, ROS can cause oxidative damage to proteins, lipids, and nucleic acids. Insulin supplies cells with antioxidant proteins capable of diffusing the oxidative effects of ROS by activating protective transcription factors such as NF-κB [246, 247, 263]. Insulin resistance not only results in reduced antioxidants but also leaves cells susceptible to ROS mediated mitochondrial collapse because of the before mentioned lack of anti-apoptotic Bcl-2 members.

The FoxO family of transcription factors is known to play a role in the cell’s response to oxidative stress, however, their prolonged activation results in apoptosis [290]. Insulin signaling inactivates FoxO transcription factors through phosphorylation by Akt. Absence of insulin signaling allows FoxO members to remain in the nucleus and sustain transcription of pro-death genes [201, 255-257].

Insulin resistance is linked to structural changes in AD by overactive GSK-3β. Neurofibrillary tangles are a pathological hallmark of AD [283] and produced by hyperphosphorylation of tau by GSK-3β. Under normal insulin signaling, GSK-3β is inactivated by Akt. Neurofibrillary tangles are one of two significant pathological characteristics of AD the other being accumulation of Aβ [291]. Aβ toxicity and aggregation into plaques has devastating consequences in the brain such as synaptic disruption [292] and inhibition of LTP [293], interference of detoxifying enzymes [294], increased ROS and oxidative stress [295], increased vulnerability to calcium overload [296] and the before mentioned effects on brain vasculature. Aβ also depresses insulin signaling [297] which results in further loss of neurotrophic support. Insulin signaling, on the other, hand is involved in Aβ clearance [298] introducing a convoluted relationship between insulin and Aβ.

Advertisement

4. Generation of Aβ

Background Aβ is a small peptide 38-43 amino acids in size long believed to have a major role in neurodegeneration and pathology of AD (for review see [299]). In sporadic AD (sAD), which accounts for over 90% of AD cases, Aβ’s role in pathogensis is still under heavy investigation. The cause of familial AD (fAD), however, has been linked to 3 mutations involved in Aβ processing; presinilins 1 and 2 (PS1/PS2), which are part of Aβ producing complexes, and amyloid precursor protein (APP) from which Aβ is derived [300]. Successive cleavages of APP by β- and γ-secretases produce toxic Aβ peptides (for review see [301]) while cleavage by α-secretase produces the neuroprotective product Secreted APP alpha (sAPPα) [302].

While the physiological role of APP remains unknown, it has been suggested that APP plays a part in neurite outgrowth, synaptogenesis, neuronal trafficking along the axon, transmembrane signal transduction, cell adhesion and calcium metabolism, all of which still require in vivo evidence (for review see [303]). APP concentrations are elevated in the brain during the prenatal period in mice which implies a role of APP in brain development [304]. In the adult brain, APP is expressed in regions of synaptic modification [304] and has been shown to increase hippocampal neuronal response to glutamate [305].

APP belongs to a family of transmembrane proteins that includes APP-like protein 1 and 2 (APPLP1/APPLP2). All APP family members are processed in a similar fashion by α, β, and γ secretases [306-308], however the Aβ domain is unique to APP. Three isoforms of APP have been identified consisting of 695, 751, or 770 amino acids which arise from alternative splicing of the same gene located on chromosome 21 [309]. APP 751 and APP 770 are expressed in most tissues and contain a 56 amino acid Kunitz Protease inhibitor (KPI) domain not found in the neuron specific 695 isoform [310, 311]. mRNA levels of the 2 KPI containing isoforms are elevated in AD brains and are associated with Aβ deposition [312].

Synthesis of APP occurs in the endoplasmic reticulum where it is then transported through the golgi apparatus to the trans golgi network where the highest concentrations of APP are found in neurons [313-315]. From there, APP can be transported in secretory vesicles to the cell surface where α-secretases are located, however, Aβ production occurs within the trans golgi network where γ-secretase complexes are thought to reside [315-318].

APP cleavage Aβ generation requires cleavage of APP by β-secretase which has been indentified to be BACE1 [319-322]. Several studies have found that regions of the brain affected by AD have elevated BACE1 activity and levels [319, 320]. Once identified, BACE1 became a popular therapeutic target for AD treatment. However, BACE1 knockout mice have shown reduced survivability after birth and were smaller than wild-type littermates [323]. BACE1 knockouts also present with hyperactive behavior [323] and other abnormalities such as hypomyelination of peripheral nerves, reduced grip strength and elevated pain sensitivity [324].

APP cleavage by BACE1 results in two fragments: sAPPβ and Beta Carboxyl Terminal Fragment (βCTF) [301, 325]. sAPPβ has been identified as a ligand for Death Receptor 6 which mediates axonal pruning and neuronal death [326]. The remaining βCTF can be cleaved by γ secretase to produce Aβ [301]. γ-secretase is a complex composed of at least 4 components: PS1 or PS2, nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2) [327, 328]. βCTF cleavage by γ secretase produces either Aβ40 or Aβ42 peptides [301]. Aβ42 is the more hydrophic and amyloidogenic of the 2 species and makes up about 10% of Aβ produced [329]. An increased Aβ42/Aβ40 ratio has consistently been shown in fAD patients suggesting that Aβ42 is critical to AD pathogensis [330, 331].

Advertisement

5. Aβ and insulin resistance

Aβ depresses insulin signaling Insulin resistance is recognized as a contributing factor in development of AD to the point that AD has been referred to as “type 3 diabetes” [4, 5]. This coincides with Aβ being a pathological hallmark of AD as Aβ contributes to insulin resistance [297]. Aβ oligomers are known impair insulin signaling in neurons [332] by competing with insulin for receptor binding sites [297] and studies have linked Aβ oligomers to decreased insulin receptor numbers [332].

Development of insulin resistance provides neurons with a dangerous dilemma as neurons rely on insulin signaling for Aβ clearance and inhibition of amyloidogenic processing. Insulin increases Aβ trafficking from the trans golgi-network leading to secretion [333]. Secretion of Aβ may be important in preventing neurodegeneration as intraneural Aβ accumulations have been found in brain regions prone to early AD in patients with mild cognitive impairment [334] and studies done with transgenic mice indicate that intracellular Aβ accumulation is an early event of the neuropathological phenotype [335-337]. Insulin signalling protects against Aβ toxicity [298] and inhibits GSK-3β activity [204] which, in addition to hyperphosphorylating tau, promotes amyloidogenic APP cleavage [160, 338].

Insulin signaling pathways in the brain are complex and depend on a delicate balance of cell activity to function properly. Accumulation of Aβ perturbs this balance resulting in insulin resistance and formation of a vicious cycle as insulin signaling is no longer able to clear and regulate Aβ. As Aβ oligomers increase, insulin resistance worsens. This cycle is perpetuated by competition between insulin and Aβ as substrates for IDE.

Insulin, Aβ and insulin degrading enzyme IDE is responsible for insulin degradation but has also been shown to degrade Aβ peptides [339-341], a process known to be decreased in AD brains [318]. Studies have shown that increased insulin signaling can increase levels of IDE [44] which can be abolished by pharmacological inhibition of PI3K. Aβ can decrease PI3K activity, [342] and thus is able to prevent its own degradation. In cases of hyperinsulinemia, excess insulin blocks IDE binding sites which further diminishes Aβ degradation [115].

In summary, Aβ contributes to insulin resistance [297, 332] by occupying binding sites on insulin receptors [297] and is associated with decreased insulin receptor numbers in neurons [332]. Decreases in insulin signaling result in increased Aβ processing as well as activation of GSK-3β which promotes Aβ processing [160, 338]. Insulin signaling impairment also leads to decreased IDE, which is needed to degrade Aβ [339-341, 343]. IDE deficiencies are exacerbated in hyperinsulinemic conditions as IDE binding sites are overloaded with excess insulin and made unavailable for Aβ [115]. Lack of insulin signaling and IDE availability allows for continued accumulation of Aβ, further depression of insulin signaling systems, increased neuronal vulnerability and further neurodegeneration.

Figure 3.

T2DM can lead to the induction of insulin resistance in the brain. (2) Reduction of insulin signaling in the brain increases the activities of GSK-3β and β secretases which (3) increase levels of toxic Aβ oligomers. Furthermore, (4) insulin resistance lowers the expression of Aβ-degrading IDE. (5) Reduced IDE then leads to increased Aβ and (6) accumulation of Aβ oligomers. T2DM also causes (7) hyperinsulinemia which exacerbates IDE deficiencies because (8) excess insulin occupies IDE binding sites rendering them unavailable for Aβ. The increased amyloidogenic processing that occurs in insulin resistance combined with decreased Aβ clearance by IDE results in a deleterious positive-feedback cycle as (9) Aβ oligomers contribute to insulin resistance in the brain. As Aβ levels continue to rise, insulin resistance worsens leading to further production of the toxic peptide.

Advertisement

6. Conclusion

By 2050 it’s estimated that over 100 million people worldwide will have AD [344] causing a substantial financial burden for health care systems. In that same time span, the annual cost of treating AD is predicated to exceed $1 trillion in the United States alone [345]. These crippling social and economical effects place increased priority for advancement of AD research.

Figure 4.

Vascular hypothesis of AD. The vascular complications have been casually linked to the progression of AD. Vascular dysfunction resulting from type 2 diabetes results in a state of cerebral hypoperfusion, leading to significant energy depletion in the brain. Neurodegeneration results in cognitive impairments and ultimately AD.

While AD remains a disease of more questions than answers, a wide array of evidence suggests a close relationship between AD and T2DM. T2DM has been characterized as having both macrovascular and microvascular complications that result in CVD. It is the vasculature that provides the tangible pathological link between T2DM and AD. Significant data has been collected in favor of the vascular hypothesis of AD, which is founded on the idea that pre-existing CVD sets into motion pathological cascades that ultimately result in AD.

AD and T2DM also share commonality in the form of insulin resistance. Lack of insulin neurotrophic support in the brain leaves neurons defenseless against oxidative stress, Aβ toxicity and apoptosis. Aβ is especially dangerous to neurons because it further depresses insulin signaling and can alter levels of protective enzymes involved in its degradation such as IDE. AD is a disease that not only causes death in weakened cells but also further depresses protective mechanisms making recovery unattainable.

Because AD affects multiple structures and pathways, it is likely that successful treatment will involve a comprehensive battery of therapeutics rather than a single therapy. T2DM plays a major role in vascular abnormalities and insulin resistance which parallel AD pathologies. As a result, further exploration of the relationship between T2DM and AD may be a promising direction of future research. Moreover, preventative measures against T2DM such as proper diet and dedication to an active lifestyle may take center stage as a means of curbing the AD epidemic.

References

  1. 1. OttAet alDiabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology, 199919371942
  2. 2. RitchieKand SLovestoneThe dementias. Lancet, 200217591766
  3. 3. FrolichLet alA disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann N Y Acad Sci, 1999290293
  4. 4. RiveraE. Jet alInsulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis, 2005247268
  5. 5. SteenEet alImpaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis, 20056380
  6. 6. SinclairA. JA. JGirlingand A. JBayerCognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services. All Wales Research into Elderly (AWARE) Study. Diabetes Res Clin Pract, 2000203212
  7. 7. PeilaRB. LRodriguezand L. JLaunerType 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes, 200212561262
  8. 8. KannelW. Band D. LMcgeeDiabetes and cardiovascular disease. The Framingham study. JAMA, 197920352038
  9. 9. StrattonI. Met alAssociation of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 2000405412
  10. 10. DefronzoR. APharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med, 20007374
  11. 11. BuseJ. Bet alPrimary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care, 2007162172
  12. 12. BellR. Det alSRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol, 2009143153
  13. 13. De La TorreJ. CIs Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol, 2004184190
  14. 14. FormichiPet alCSF Biomarkers Profile in CADASIL-A Model of Pure Vascular Dementia: Usefulness in Differential Diagnosis in the Dementia Disorder. Int J Alzheimers Dis, 2010. 2010
  15. 15. JagustW. Jet alThe Alzheimer’s Disease Neuroimaging Initiative positron emission tomography core. Alzheimers Dement, 2010221229
  16. 16. PakrasiSand J. T. OBrienEmission tomography in dementia. Nucl Med Commun, 2005189196
  17. 17. KahnA. Met alInsulin acutely inhibits cultured vascular smooth muscle cell contraction by a nitric oxide synthase-dependent pathway. Hypertension, 1997928933
  18. 18. BolotinaV. Met alNitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature, 1994850853
  19. 19. PotenzaM. Aet alInsulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol, 2005H813H822
  20. 20. PotenzaM. Aet alTreatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance. Diabetes, 200635943603
  21. 21. FormosoGet alDehydroepiandrosterone mimics acute actions of insulin to stimulate production of both nitric oxide and endothelin 1 via distinct phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-dependent pathways in vascular endothelium. Mol Endocrinol, 200611531163
  22. 22. WildSet alGlobal prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 200410471053
  23. 23. BiesselsG. Jet alRisk of dementia in diabetes mellitus: a systematic review. Lancet Neurol, 20066474
  24. 24. LuF. PK. PLinand H. KKuoDiabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PLoS One, 2009e4144
  25. 25. ProfennoL. AA. PPorsteinssonand S. VFaraoneMeta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry, 2012505512
  26. 26. AhtiluotoSet alDiabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology, 201011951202
  27. 27. KalariaR. NNeurodegenerative disease: Diabetes, microvascular pathology and Alzheimer disease. Nat Rev Neurol, 2009305306
  28. 28. ZlokovicB. VThe blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 2008178201
  29. 29. ZlokovicB. VNeurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci, 2011723738
  30. 30. MoskowitzM. AE. HLoand CIadecolaThe science of stroke: mechanisms in search of treatments. Neuron, 2010181198
  31. 31. BeckmanJ. AM. ACreagerand PLibbyDiabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA, 200225702581
  32. 32. MastersS. LELatzand L. A. ONeillThe inflammasome in atherosclerosis and type 2 diabetes. Sci Transl Med, 201181ps17
  33. 33. KleinRHyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care, 1995258268
  34. 34. TurnerR. Cet alRisk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ, 1998823828
  35. 35. KuusistoJet alNIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes, 1994960967
  36. 36. LehtoSet alPredictors of stroke in middle-aged patients with non-insulin-dependent diabetes. Stroke, 19966368
  37. 37. ChengGet alDiabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J, 2012484491
  38. 38. JansonJet alIncreased risk of type 2 diabetes in Alzheimer disease. Diabetes, 2004474481
  39. 39. LeibsonC. Let alRisk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol, 1997301308
  40. 40. PansariKAGuptaand PThomasAlzheimer’s disease and vascular factors: facts and theories. Int J Clin Pract, 2002197203
  41. 41. De La MonteS. MInsulin resistance and Alzheimer’s disease. BMB Rep, 2009475481
  42. 42. KimBand E. LFeldmanInsulin resistance in the nervous system. Trends Endocrinol Metab, 2012133141
  43. 43. KimBet alCortical neurons develop insulin resistance and blunted Akt signaling: a potential mechanism contributing to enhanced ischemic injury in diabetes. Antioxid Redox Signal, 201118291839
  44. 44. ZhaoZet alInsulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer’s disease. Neurobiol Aging, 2007824830
  45. 45. StockerRand J. FKeaneyJr., Role of oxidative modifications in atherosclerosis. Physiol Rev, 200413811478
  46. 46. JiangZ. Yet alCharacterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest, 1999447457
  47. 47. CusiKet alInsulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest, 2000311320
  48. 48. PiattiP. Met alHypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans. Diabetes, 1996316321
  49. 49. SarkarRet alNitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res, 1996225230
  50. 50. KubesPMSuzukiand D. NGrangerNitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A, 199146514655
  51. 51. ZeiherA. Met alNitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res, 1995980986
  52. 52. NomuraSet alSignificance of chemokines and activated platelets in patients with diabetes. Clin Exp Immunol, 2000437443
  53. 53. CollinsTand M. ICybulskyNF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest, 2001255264
  54. 54. PetersenK. Fand G. IShulmanEtiology of insulin resistance. Am J Med, 2006Suppl 1): S10S16
  55. 55. RodenMet alMechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest, 199628592865
  56. 56. SteinbergH. Oand A. DBaronVascular function, insulin resistance and fatty acids. Diabetologia, 2002623634
  57. 57. WangX. Let alFree fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes, 200623012310
  58. 58. NaruseKet alActivation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes, 2006691698
  59. 59. KimFet alFree fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol, 2005989994
  60. 60. MuniyappaRet alCardiovascular actions of insulin. Endocr Rev, 2007463491
  61. 61. DuX. Let alHyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest, 200113411348
  62. 62. SchnyderBet alRapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport. Am J Physiol Endocrinol Metab, 2002E87E94
  63. 63. BarbaRet alPoststroke dementia : clinical features and risk factors. Stroke, 200014941501
  64. 64. BretelerM. MVascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging, 2000153160
  65. 65. HofmanAet alAtherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet, 1997151154
  66. 66. BarnesD. Eand KYaffeThe projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol, 2011819828
  67. 67. ArenillasJ. Fet alMetabolic syndrome and resistance to IV thrombolysis in middle cerebral artery ischemic stroke. Neurology, 2008190195
  68. 68. De AngelisMet alPrevalence of carotid stenosis in type 2 diabetic patients asymptomatic for cerebrovascular disease. Diabetes Nutr Metab, 20034855
  69. 69. LetonjaM. Set alAssociation of the C242T polymorphism in the NADPH oxidase 22phox gene with carotid atherosclerosis in Slovenian patients with type 2 diabetes. Mol Biol Rep, 2012
  70. 70. PalomoIet alHemostasis alterations in metabolic syndrome (review). Int J Mol Med, 2006969974
  71. 71. AlessiM. Cand IJuhan-vagueMetabolic syndrome, haemostasis and thrombosis. Thromb Haemost, 20089951000
  72. 72. KalariaR. Nand CBallardOverlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord, 1999Suppl 3: S115S123
  73. 73. HenonHet alPreexisting dementia in stroke patients. Baseline frequency, associated factors, and outcome. Stroke, 199724292436
  74. 74. KokmenEet alDementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960-1984). Neurology, 1996154159
  75. 75. PasquierFDLeysand PScheltensThe influence of coincidental vascular pathology on symptomatology and course of Alzheimer’s disease. J Neural Transm Suppl, 1998117127
  76. 76. FerrucciLet alCognitive impairment and risk of stroke in the older population. J Am Geriatr Soc, 1996237241
  77. 77. GaleC. RC. NMartynand CCooperCognitive impairment and mortality in a cohort of elderly people. BMJ, 1996608611
  78. 78. CaiYet albeta-Secretase-1 elevation in aged monkey and Alzheimer’s disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and beta-amyloid accumulation. Eur J Neurosci, 201012231238
  79. 79. BeachT. Get alCircle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol, 20071321
  80. 80. RoherA. Eet alCircle of willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol, 200320552062
  81. 81. HonigL. SWKukulland RMayeuxAtherosclerosis and AD: analysis of data from the US National Alzheimer’s Coordinating Center. Neurology, 2005494500
  82. 82. GrammasPNeurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer’s disease. J Neuroinflammation, 201126
  83. 83. KawaiMet alThe relationship of amyloid plaques to cerebral capillaries in Alzheimer’s disease. Am J Pathol, 199014351446
  84. 84. KalariaR. NThe role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging, 2000321330
  85. 85. KalariaR. Nand PHederaDifferential degeneration of the cerebral microvasculature in Alzheimer’s disease. Neuroreport, 1995477480
  86. 86. De La TorreJ. CCerebromicrovascular pathology in Alzheimer’s disease compared to normal aging. Gerontology, 19972643
  87. 87. BueeLet alPathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol, 1994469480
  88. 88. ChristovAet alStructural changes in Alzheimer’s disease brain microvessels. Curr Alzheimer Res, 2008392395
  89. 89. DaviesD. Cand J. AHardyBlood brain barrier in ageing and Alzheimer’s disease. Neurobiol Aging, 19884648
  90. 90. KalariaR. Nand A. BPaxIncreased collagen content of cerebral microvessels in Alzheimer’s disease. Brain Res, 1995349352
  91. 91. MastersC. Land KBeyreutherThe blood-brain barrier in Alzheimer’s disease and normal aging. Neurobiol Aging, 19884344
  92. 92. ClaudioLUltrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer’s disease patients. Acta Neuropathol, 1996614
  93. 93. YanS. Det alRAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature, 1996685691
  94. 94. Van BeekA. Het alCerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab, 200810711085
  95. 95. RancillacAHGeoffroyand JRossierImpaired neurovascular coupling in the APPxPS1 mouse model of Alzheimer’s disease. Curr Alzheimer Res, 2012
  96. 96. ClaassenJ. Aet alTranscranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing. J Appl Physiol, 2007870877
  97. 97. LeeS. TK. HJungand Y. SLeeDecreased vasomotor reactivity in Alzheimer’s disease. J Clin Neurol, 20071823
  98. 98. Menendez-gonzalezMet alVasomotor reactivity is similarly impaired in patients with Alzheimer’s disease and patients with amyloid hemorrhage. J Neuroimaging, 2011e83e85
  99. 99. BaroneF. Cet alVascular cognitive impairment: dementia biology and translational animal models. Curr Opin Investig Drugs, 2009624637
  100. 100. FarkasEP. GLuitenand FBariPermanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007162180
  101. 101. VicenteEet alAstroglial and cognitive effects of chronic cerebral hypoperfusion in the rat. Brain Res, 2009204212
  102. 102. LiuHet alRegulation of beta-amyloid level in the brain of rats with cerebrovascular hypoperfusion. Neurobiol Aging, 2011826e31-42.
  103. 103. ZhiyouCet alUpregulation of BACE1 and beta-amyloid protein mediated by chronic cerebral hypoperfusion contributes to cognitive impairment and pathogenesis of Alzheimer’s disease. Neurochem Res, 200912261235
  104. 104. KalariaR. Net alThe amyloid precursor protein in ischemic brain injury and chronic hypoperfusion. Ann N Y Acad Sci, 1993190193
  105. 105. StephensonD. TKRashand J. AClemensAmyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. Brain Res, 1992128135
  106. 106. WenYet alIncreased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res, 200418
  107. 107. ZhangXet alHypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem, 20071087310880
  108. 108. TescoGet alDepletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron, 2007721737
  109. 109. ZhangYet alMutant ubiquitin-mediated beta-secretase stability via activation of caspase-3 is related to beta-amyloid accumulation in ischemic striatum in rats. J Cereb Blood Flow Metab, 2010566575
  110. 110. LiLet alHypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging, 200910911098
  111. 111. OkamotoYet alCerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol, 2012381394
  112. 112. DeaneRet alRAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med, 2003907913
  113. 113. MinersJ. Set alDecreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol, 200610121021
  114. 114. WeeraratnaA. Tet alAlterations in immunological and neurological gene expression patterns in Alzheimer’s disease tissues. Exp Cell Res, 2007450461
  115. 115. QiuW. Qand M. FFolsteinInsulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging, 2006190198
  116. 116. HayashiSet alAlzheimer disease-associated peptide, amyloid beta40, inhibits vascular regeneration with induction of endothelial autophagy. Arterioscler Thromb Vasc Biol, 200919091915
  117. 117. DonniniSet alAbeta peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis. FASEB J, 201023852395
  118. 118. GentileM. Tet alMechanisms of soluble beta-amyloid impairment of endothelial function. J Biol Chem, 20044813548142
  119. 119. HuangZet alEnlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab, 1996981987
  120. 120. ChristieRet alStructural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol, 200110651071
  121. 121. MerliniMet alVascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol, 2008293311
  122. 122. TongPet alInsulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles. J Clin Invest, 2001371381
  123. 123. ArvanitakisZet alDiabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology, 200619601965
  124. 124. LuchsingerJ. AType 2 diabetes, related conditions, in relation and dementia: an opportunity for prevention? J Alzheimers Dis, 2010723736
  125. 125. CurbJ. Det alLongitudinal association of vascular and Alzheimer’s dementias, diabetes, and glucose tolerance. Neurology, 1999971975
  126. 126. XuW. Let alDiabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology, 200411811186
  127. 127. BrookmeyerRSGrayand CKawasProjections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health, 199813371342
  128. 128. ClarkC. Met alEarlier onset of Alzheimer disease symptoms in latino individuals compared with anglo individuals. Arch Neurol, 2005774778
  129. 129. KorczynA. DMixed dementia--the most common cause of dementia. Ann N Y Acad Sci, 2002129134
  130. 130. GoldbergIet alMicroembolism, silent brain infarcts and dementia. J Neurol Sci, 2012
  131. 131. ErkinjunttiTClinical deficits of Alzheimer’s disease with cerebrovascular disease and probable VaD. Int J Clin Pract Suppl, 20011423
  132. 132. RomanG. Cand D. RRoyallExecutive control function: a rational basis for the diagnosis of vascular dementia. Alzheimer Dis Assoc Disord, 1999Suppl 3: S69S80
  133. 133. BarberRet alWhite matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry, 19996672
  134. 134. CordonnierCet alPrevalence and severity of microbleeds in a memory clinic setting. Neurology, 200613561360
  135. 135. ZareiMet alRegional white matter integrity differentiates between vascular dementia and Alzheimer disease. Stroke, 2009773779
  136. 136. CacabelosRet alCerebrovascular risk factors in Alzheimer’s disease: brain hemodynamics and pharmacogenomic implications. Neurol Res, 2003567580
  137. 137. GorelickP. BRisk factors for vascular dementia and Alzheimer disease. Stroke, 2004Suppl 1): 26202622
  138. 138. SabayanBet alCerebrovascular hemodynamics in Alzheimer’s disease and vascular dementia: a meta-analysis of transcranial Doppler studies. Ageing Res Rev, 2012271277
  139. 139. AltmanRand J. CRutledgeThe vascular contribution to Alzheimer’s disease. Clin Sci (Lond), 2010407421
  140. 140. VintersH. VCerebral amyloid angiopathy. A critical review. Stroke, 1987311324
  141. 141. KalariaR. Net alProduction and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer’s disease. Brain Res Mol Brain Res, 19965868
  142. 142. KosunenOet alDiagnostic accuracy of Alzheimer’s disease: a neuropathological study. Acta Neuropathol, 1996185193
  143. 143. OlichneyJ. Met alCerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol, 1995702708
  144. 144. PremkumarD. Ret alApolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer’s disease. Am J Pathol, 199620832095
  145. 145. KalariaRSimilarities between Alzheimer’s disease and vascular dementia. J Neurol Sci, 20022934
  146. 146. FrisoniG. Bet alApolipoprotein E epsilon 4 allele in Alzheimer’s disease and vascular dementia. Dementia, 1994240242
  147. 147. SnowdonD. Aet alBrain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA, 1997813817
  148. 148. BondyC. Aand C. MChengSignaling by insulin-like growth factor 1 in brain. Eur J Pharmacol, 20042531
  149. 149. YamaguchiYet alLigand-binding properties of the two isoforms of the human insulin receptor. Endocrinology, 199311321138
  150. 150. KasugaMF. AKarlssonand C. RKahnInsulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science, 1982185187
  151. 151. JacobsSet alSomatomedin-C stimulates the phosphorylation of the beta-subunit of its own receptor. J Biol Chem, 198395819584
  152. 152. RubinJ. BM. AShiaand P. FPilchStimulation of tyrosine-specific phosphorylation in vitro by insulin-like growth factor I. Nature, 1983438440
  153. 153. SchechterRet alDevelopmental regulation of insulin in the mammalian central nervous system. Brain Res, 19922737
  154. 154. SchechterRet alPreproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res, 19961627
  155. 155. SchechterRand MAbboudNeuronal synthesized insulin roles on neural differentiation within fetal rat neuron cell cultures. Brain Res Dev Brain Res, 20014149
  156. 156. CokerG. Trd, et alAnalysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues. Brain Res Mol Brain Res, 19909398
  157. 157. DevaskarS. Uet alInsulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem, 199484458454
  158. 158. BanksW. AThe source of cerebral insulin. Eur J Pharmacol, 2004512
  159. 159. BurnsJ. Met alPeripheral insulin and brain structure in early Alzheimer disease. Neurology, 200710941104
  160. 160. Salkovic-petrisicMand SHoyerCentral insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl, 2007217233
  161. 161. ErolAAn integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer’s disease. J Alzheimers Dis, 2008241253
  162. 162. ParkC. RCognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev, 2001311323
  163. 163. EbinaYet alThe human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell, 1985747758
  164. 164. UllrichAet alHuman insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature, 1985756761
  165. 165. FrascaFet alInsulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol, 199932783288
  166. 166. MosthafLet alFunctionally distinct insulin receptors generated by tissue-specific alternative splicing. Embo J, 199024092413
  167. 167. HedoJ. Aet alDirect demonstration of glycosylation of insulin receptor subunits by biosynthetic and external labeling: evidence for heterogeneity. Proc Natl Acad Sci U S A, 198147914795
  168. 168. MassagueJP. FPilchand M. PCzechA unique proteolytic cleavage site on the beta subunit of the insulin receptor. J Biol Chem, 198131823190
  169. 169. SiegelT. Wet alPurification and properties of the human placental insulin receptor. J Biol Chem, 198192669273
  170. 170. KanzakiMInsulin receptor signals regulating GLUT4 translocation and actin dynamics. Endocr J, 2006267293
  171. 171. FrattaliA. Land J. EPessinRelationship between alpha subunit ligand occupancy and beta subunit autophosphorylation in insulin/insulin-like growth factor-1 hybrid receptors. J Biol Chem, 199373937400
  172. 172. LeeJet alInsulin receptor autophosphorylation occurs asymmetrically. J Biol Chem, 199340924098
  173. 173. LeeJand P. FPilchThe insulin receptor: structure, function, and signaling. Am J Physiol, 1994Pt 1): C319C334
  174. 174. WhiteM. Fet alMutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell, 1988641649
  175. 175. WhiteM. FThe IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem, 1998311
  176. 176. MyersM. GJr., et alIRS-1 activates phosphatidylinositol 3’-kinase by associating with src homology 2 domains of 85Proc Natl Acad Sci U S A, 1992p. 10350-4.
  177. 177. VirkamakiAKUekiand C. RKahnProtein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest, 1999931943
  178. 178. MayerB. Jet alA putative modular domain present in diverse signaling proteins. Cell, 1993629630
  179. 179. YenushLet alThe pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. J Biol Chem, 19962430024306
  180. 180. CofferP. Jand J. RWoodgettMolecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem, 1991475481
  181. 181. BurgeringB. Mand P. JCofferProtein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature, 1995599602
  182. 182. AndjelkovicMet alActivation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci U S A, 199656995704
  183. 183. KohnA. DFTakeuchiand R. ARothAkt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem, 19962192021926
  184. 184. BellacosaAet alAkt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene, 1998313325
  185. 185. SoskicVet alFunctional proteomics analysis of signal transduction pathways of the platelet-derived growth factor beta receptor. Biochemistry, 199917571764
  186. 186. AlessiD. Ret alPhosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol, 1997776789
  187. 187. StokoeDet alDual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science, 1997567570
  188. 188. CurrieR. Aet alRole of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J, 1999Pt 3): 575583
  189. 189. AlessiD. Ret alMechanism of activation of protein kinase B by insulin and IGF-1. EMBO J, 199665416551
  190. 190. AlessiD. Ret alCharacterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol, 1997261269
  191. 191. SarbassovD. Det alPhosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 200510981101
  192. 192. YangJet alCrystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol, 2002940944
  193. 193. CardoneM. Het alRegulation of cell death protease caspase-9 by phosphorylation. Science, 199813181321
  194. 194. DattaS. Ret alAkt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997231241
  195. 195. del PesoL., et al., Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science, 1997687689
  196. 196. Blume-jensenPRJanknechtand THunterThe kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr Biol, 1998779782
  197. 197. WangH. Get alCa2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science, 1999339343
  198. 198. DuKand MMontminyCREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem, 19983237732379
  199. 199. KaneL. Pet alInduction of NF-kappaB by the Akt/PKB kinase. Curr Biol, 1999601604
  200. 200. BiggsW. Hrd, et alProtein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci U S A, 199974217426
  201. 201. BrunetAet alAkt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 1999857868
  202. 202. KopsG. Jet alDirect control of the Forkhead transcription factor AFX by protein kinase B. Nature, 1999630634
  203. 203. ReadD. Eand A. MGormanInvolvement of Akt in neurite outgrowth. Cell Mol Life Sci, 200929752984
  204. 204. BhatR. Vet alRegulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A, 20001107411079
  205. 205. LlambiFet alA unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell, 2011517531
  206. 206. GreenD. Rand J. CReedMitochondria and apoptosis. Science, 199813091312
  207. 207. ReedJ. CBcl-2 family proteins. Oncogene, 199832253236
  208. 208. PastorinoJ. Get alFunctional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem, 19993173431739
  209. 209. AntonssonBet alBax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J, 2000Pt 2: 271278
  210. 210. RongYand C. WDistelhorstBcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol, 20087391
  211. 211. LemastersJ. Jet alMitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta, 200913951401
  212. 212. ParadiesGet alRole of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium, 2009643650
  213. 213. Bossy-wetzelEand D. RGreenApoptosis: checkpoint at the mitochondrial frontier. Mutat Res, 1999243251
  214. 214. TorneroDIPosadasand VCenaBcl-x(L) blocks a mitochondrial inner membrane channel and prevents Ca2+ overload-mediated cell death. PLoS One, 2011e20423
  215. 215. YangEet alBad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell, 1995285291
  216. 216. OttilieSet alDimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. J Biol Chem, 19973086630872
  217. 217. ZhaJet alBH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J Biol Chem, 19972410124104
  218. 218. DattaS. RABrunetand M. EGreenbergCellular survival: a play in three Akts. Genes Dev, 199929052927
  219. 219. TsujimotoYRole of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells, 1998697707
  220. 220. CrynsVand JYuanProteases to die for. Genes Dev, 199815511570
  221. 221. PettmannBand C. EHendersonNeuronal cell death. Neuron, 1998633647
  222. 222. MerryD. Eand S. JKorsmeyerBcl-2 gene family in the nervous system. Annu Rev Neurosci, 1997245267
  223. 223. MurphyA. Net alBcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci U S A, 199698939898
  224. 224. VercesiA. Eet alThe role of reactive oxygen species in mitochondrial permeability transition. Biosci Rep, 19974352
  225. 225. EllerbyL. Met alShift of the cellular oxidation-reduction potential in neural cells expressing Bcl-2. J Neurochem, 199612591267
  226. 226. EspostiM. Det alBcl-2 and mitochondrial oxygen radicals. New approaches with reactive oxygen species-sensitive probes. J Biol Chem, 19992983129837
  227. 227. SingletonJ. RV. MDixitand E. LFeldmanType I insulin-like growth factor receptor activation regulates apoptotic proteins. J Biol Chem, 19963179131794
  228. 228. MinshallCet alIL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors. J Immunol, 199712251232
  229. 229. TamataniMSOgawaand MTohyamaRoles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors. Brain Res Mol Brain Res, 19982739
  230. 230. PugazhenthiSet alInsulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein. J Biol Chem, 19992752927535
  231. 231. ShiehP. Bet alIdentification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron, 1998727740
  232. 232. TaoXet alCa2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron, 1998709726
  233. 233. HuYand S. JRussekBDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem, 2008117
  234. 234. FuWCLuand M. PMattsonTelomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. J Neurosci, 20021071010719
  235. 235. RoheMet alBrain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci, 20091547215478
  236. 236. ArancibiaSet alProtective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis, 2008316326
  237. 237. LaskeCet alBDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res, 2007387394
  238. 238. LeeJ. Get alDecreased serum brain-derived neurotrophic factor levels in elderly korean with dementia. Psychiatry Investig, 2009299305
  239. 239. ForlenzaO. VB. SDinizand W. FGattazDiagnosis and biomarkers of predementia in Alzheimer’s disease. BMC Med, 20108: 89
  240. 240. ForlenzaO. Vet alClinical and biological predictors of Alzheimer’s disease in patients with amnestic mild cognitive impairment. Rev Bras Psiquiatr, 2010216222
  241. 241. ForlenzaO. Vet alEffect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry, 2010774780
  242. 242. GunstadJet alSerum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatr Psychiatry Neurol, 2008166170
  243. 243. MaggirwarS. Bet alNerve growth factor-dependent activation of NF-kappaB contributes to survival of sympathetic neurons. J Neurosci, 19981035610365
  244. 244. RiccioAet alMediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science, 199923582361
  245. 245. MinchevaSet alThe canonical nuclear factor-kappaB pathway regulates cell survival in a developmental model of spinal cord motoneurons. J Neurosci, 201164936503
  246. 246. MaeharaKTHasegawaand K. IIsobeA NF-kappaB 65subunit is indispensable for activating manganese superoxide: dismutase gene transcription mediated by tumor necrosis factor-alpha. J Cell Biochem, 2000p. 474-86.
  247. 247. RojoA. Iet alRegulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kappaB. J Neurosci, 200473247334
  248. 248. TamataniMet alTumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem, 199985318538
  249. 249. MayM. Jand SGhoshRelN. F-k. a. p. p. a Band IKappaBProteinsan overview. Semin Cancer Biol, 19976373
  250. 250. MercurioFand A. MManningMultiple signals converging on NF-kappaB. Curr Opin Cell Biol, 1999226232
  251. 251. PerkinsN. DIntegrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol, 20074962
  252. 252. OzesO. Net alNF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature, 19998285
  253. 253. Van Der HeideL. PM. FHoekmanand M. PSmidtThe ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J, 2004Pt 2): 297309
  254. 254. MiyashitaTand J. CReedTumor suppressor 53is a direct transcriptional activator of the human bax gene. Cell, 1995p. 293-9.
  255. 255. ReifKB. MBurgeringand D. ACantrellPhosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and 70S6 kinase. J Biol Chem, 1997p. 14426-33.
  256. 256. StahlMet alThe forkhead transcription factor FoxO regulates transcription of 27Kip1and Bim in response to IL-2. J Immunol, 2002p. 5024-31.
  257. 257. DijkersP. Fet alExpression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol, 200012011204
  258. 258. GrahamS. Hand JChenProgrammed cell death in cerebral ischemia. J Cereb Blood Flow Metab, 200199109
  259. 259. YamaguchiHand H. GWangBcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. J Biol Chem, 20024160441612
  260. 260. YamaguchiAet alAkt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of 53J Biol Chem, 2001p. 5256-64.
  261. 261. KowaltowskiA. JA. EVercesiand GFiskumBcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides. Cell Death Differ, 2000903910
  262. 262. AloyzR. Set al53is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J Cell Biol, 1998p. 1691-703.
  263. 263. JaworskiJet alControl of dendritic arborization by the phosphoinositide-3’-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci, 20051130011312
  264. 264. KumarVet alRegulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci, 20051128811299
  265. 265. YoshimuraTet alRas regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. Biochem Biophys Res Commun, 20066268
  266. 266. LimC. Sand R. SWalikonisHepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal, 2008825835
  267. 267. ZhengJet alClathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem, 20081328013288
  268. 268. MarkusAJZhongand W. DSniderRaf and akt mediate distinct aspects of sensory axon growth. Neuron, 20026576
  269. 269. MillsJet alRole of integrin-linked kinase in nerve growth factor-stimulated neurite outgrowth. J Neurosci, 200316381648
  270. 270. TuckerB. AMRahimtulaand K. MMearowLaminin and growth factor receptor activation stimulates differential growth responses in subpopulations of adult DRG neurons. Eur J Neurosci, 2006676690
  271. 271. TuckerB. AMRahimtulaand K. MMearowSrc and FAK are key early signalling intermediates required for neurite growth in NGF-responsive adult DRG neurons. Cell Signal, 2008241257
  272. 272. CrossD. Aet alInhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995785789
  273. 273. SalasT. Ret alAlleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei. J Biol Chem, 20034133841346
  274. 274. AsnaghiLet alBcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene, 200457815791
  275. 275. KonishiHet alIdentification of peripherin as a Akt substrate in neurons. J Biol Chem, 20072349123499
  276. 276. KimHet alDelta-catenin-induced dendritic morphogenesis. An essential role of 190RhoGEFinteraction through Akt1-mediated phosphorylation. J Biol Chem, 2008p. 977-87.
  277. 277. KonishiHet alActivation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett, 1997493498
  278. 278. MurashovA. Ket alCrosstalk between 38Hsp25 and Akt in spinal motor neurons after sciatic nerve injury. Brain Res Mol Brain Res, 2001p. 199-208.
  279. 279. FrameSand PCohenGSK3 takes centre stage more than 20 years after its discovery. Biochem J, 2001Pt 1): 116
  280. 280. GrimesC. Aand R. SJopeThe multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol, 2001391426
  281. 281. DobleB. Wand J. RWoodgettGSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci, 2003Pt 7): 11751186
  282. 282. HooperCRKillickand SLovestoneThe GSK3 hypothesis of Alzheimer’s disease. J Neurochem, 200814331439
  283. 283. IqbalKet alMechanisms of tau-induced neurodegeneration. Acta Neuropathol, 20095369
  284. 284. MandelkowE. Met alClogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging, 200310791085
  285. 285. BrewsterJ. Let alEndoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3 beta and a caspase-9-dependent apoptosis in cerebellar granule neurons. Mol Cell Neurosci, 2006242253
  286. 286. DuyckaertsCBDelatourand M. CPotierClassification and basic pathology of Alzheimer disease. Acta Neuropathol, 2009536
  287. 287. TakashimaAAmyloid-beta, tau, and dementia. J Alzheimers Dis, 2009729736
  288. 288. WangJ. Met alReduction of ischemic brain injury by topical application of insulin-like growth factor-I after transient middle cerebral artery occlusion in rats. Brain Res, 2000381385
  289. 289. St-pierreJet alTopology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem, 20024478444790
  290. 290. BarthelADSchmolland T. GUntermanFoxO proteins in insulin action and metabolism. Trends Endocrinol Metab, 2005183189
  291. 291. ZetterbergHL. OWahlundand KBlennowCerebrospinal fluid markers for prediction of Alzheimer’s disease. Neurosci Lett, 20036769
  292. 292. LacorP. Net alSynaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci, 20041019110200
  293. 293. WalshD. Met alNaturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 2002535539
  294. 294. TillementLLLecanuand VPapadopoulosAlzheimer’s disease: effects of beta-amyloid on mitochondria. Mitochondrion. 11(1): 1321
  295. 295. AbramovA. YLCanevariand M. RDuchenCalcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochim Biophys Acta, 20048187
  296. 296. MattsonM. Pet albeta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci, 1992376389
  297. 297. XieLet alAlzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci, 2002RC221
  298. 298. MessierCand KTeutenbergThe role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer’s disease. Neural Plast, 2005311328
  299. 299. ThinakaranGand E. HKooAmyloid precursor protein trafficking, processing, and function. J Biol Chem, 20082961529619
  300. 300. RocchiAet alCausative and susceptibility genes for Alzheimer’s disease: a review. Brain Res Bull, 2003124
  301. 301. ZhangY. Wet alAPP processing in Alzheimer’s disease. Mol Brain. 4: 3
  302. 302. De StrooperBand WAnnaertProteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci, 2000Pt 11): 18571870
  303. 303. ZhengHand E. HKooThe amyloid precursor protein: beyond amyloid. Mol Neurodegener, 20065
  304. 304. LofflerJand GHuberBeta-amyloid precursor protein isoforms in various rat brain regions and during brain development. J Neurochem, 199213161324
  305. 305. Tominaga-yoshinoKet alNeurotoxic and neuroprotective effects of glutamate are enhanced by introduction of amyloid precursor protein cDNA. Brain Res, 2001121130
  306. 306. WascoWet alIsolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet, 199395100
  307. 307. WascoWet alIdentification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci U S A, 19921075810762
  308. 308. CoulsonE. Jet alWhat the evolution of the amyloid protein precursor supergene family tells us about its function. Neurochem Int, 2000175184
  309. 309. GoateAet alSegregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 1991704706
  310. 310. Rohan de SilvaH.A., et al., Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes. Brain Res Mol Brain Res, 1997147156
  311. 311. KangJand BMuller-hillDifferential splicing of Alzheimer’s disease amyloid A4 precursor RNA in rat tissues: PreA4(695) mRNA is predominantly produced in rat and human brain. Biochem Biophys Res Commun, 199011921200
  312. 312. Menendez-gonzalezMet alAPP processing and the APP-KPI domain involvement in the amyloid cascade. Neurodegener Dis, 2005277283
  313. 313. XuHet alGeneration of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci U S A, 199737483752
  314. 314. HartmannTet alDistinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med, 199710161020
  315. 315. GreenfieldJ. Pet alEndoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci U S A, 1999742747
  316. 316. CupersPet alThe discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J Cell Biol, 2001731740
  317. 317. KovacsD. Met alAlzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med, 1996224229
  318. 318. PerezAet alDegradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem Res, 2000247255
  319. 319. SinhaSet alPurification and cloning of amyloid precursor protein beta-secretase from human brain. Nature, 1999537540
  320. 320. VassarRet alBeta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 1999735741
  321. 321. YanRet alMembrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature, 1999533537
  322. 322. LauK. Fet alX11 alpha and x11 beta interact with presenilin-1 via their PDZ domains. Mol Cell Neurosci, 2000557565
  323. 323. DominguezDet alPhenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem, 20053079730806
  324. 324. HuXet alBace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci, 200615201525
  325. 325. ChowV. Wet alAn overview of APP processing enzymes and products. Neuromolecular Med. 12(1): 112
  326. 326. NikolaevAet alAPP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature, 2009981989
  327. 327. KimberlyW. Tet alGamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A, 200363826387
  328. 328. TakasugiNet alThe role of presenilin cofactors in the gamma-secretase complex. Nature, 2003438441
  329. 329. BurdickDet alAssembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J Biol Chem, 1992546554
  330. 330. ScheunerDet alSecreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med, 1996864870
  331. 331. BorcheltD. Ret alFamilial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron, 199610051013
  332. 332. ZhaoW. Qet alAmyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J, 2008246260
  333. 333. GaspariniLet alStimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci, 200125612570
  334. 334. GourasG. Ket alIntraneuronal Abeta42 accumulation in human brain. Am J Pathol, 20001520
  335. 335. OddoSet alTriple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 2003409421
  336. 336. OddoSet alA dynamic relationship between intracellular and extracellular pools of Abeta. Am J Pathol, 2006184194
  337. 337. OakleyHet alIntraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci, 20061012910140
  338. 338. PhielC. Jet alGSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature, 2003435439
  339. 339. FarrisWet alPartial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol, 200414251434
  340. 340. VekrellisKet alNeurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci, 200016571665
  341. 341. FarrisWet alInsulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A, 200341624167
  342. 342. TakashimaAet alExposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett, 19963336
  343. 343. ZhaoLet alInsulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci, 20041112011126
  344. 344. BrookmeyerRet alForecasting the global burden of Alzheimer’s disease. Alzheimers Dement, 2007186191
  345. 345. VellasBet alDisease-modifying trials in Alzheimer’s disease: a European task force consensus. Lancet Neurol, 20075662

Written By

Brent D. Aulston, Gary L. Odero, Zaid Aboud and Gordon W. Glazner

Submitted: 18 September 2012 Published: 27 February 2013