1. Introduction
Alzheimer’s disease (AD) represents the so-called “storage disorder” of amyloid β (Aβ). The AD brain contains soluble and insoluble Aβ, both of which have been hypothesized to underlie the development of cognitive deficits or dementia [1-3]. The steady-state level of Aβ is controlled by the generation of Aβ from its precursor, the degradation of Aβ within the brain, and transport of Aβ out of the brain. The imbalance among three metabolic pathways results in excessive accumulation and deposition of Aβ in the brain, which may trigger a complex downstream cascade (e.g., primary amyloid plaque formation or secondary tauopathy and neurodegeneration) leading to memory loss or dementia in AD. Accumulated lines of evidence indicate that such a memory loss represents a synaptic failure caused directly by soluble Aβ oligomers (AβOs) [4-6], whereas amyloid fibrils may cause neuronal injury indirectly via microglial activation [7]. Many attentions are paid to understand the mechanism underlying the neurotoxic action of AβOs so far. However, the exact metabolic conditions controlling the
Several lines of evidence indicated that lipidic environments in the central nervous system (CNS) represent one of the prevailing metabolic conditions. We then hypothesized that an alteration of the lipoprotein-soluble Aβ interaction in the CNS is capable of initiating and/or accelerating the cascade favoring Aβ assembly [8]. We found that dissociation of Aβ42 from lipoprotein in the cerebrospinal fluid from AD accelerates Aβ42 assembly [9]. Thus, lipoprotein is a key molecule to maintain monomeric soluble Aβ42 in CNS.
In this chapter, we review the issue regarding how lipoprotein and apolipoproteins contribute to physiological metabolic conditions. Then, we focus on how they constitute the AD-related metabolic conditions in the CNS. We are certain that these points of view introduce a novel approach to find a therapeutic intervention for AD.
2. Lipoproteins, apolipoproteins, and Aβ metabolism in the CNS
In the CNS, we need to be aware that cholesterol metabolism is quite different from that in systemic circulation. Lipidic environments in the CNS were regulated by HDL-like lipoproteins, mainly lipidated apolipoprotein E (apoE), which is in charge of cholesterol transport to and from neurons [10, 11]. This is also the case in lipidated apolipoprotein J (apoJ) [12]. In addition to lipid trafficking, apoE or apoJ as a form of HDL-like lipoprotein plays a major role in Aβ metabolism in the CNS. Both apolipoproteins are well known as major carrier proteins for Aβ [13-17]. Interestingly, transgenic mouse models of AD (apoE-/-/apoJ-/-) revealed that both apolipoproteins regulate in a cooperative manner the clearance and the deposition of Aβ in brain [18]. The hypothetical pathways involved in the clearance of CNS Aß are efflux of Aß into the plasma via blood-brain barrier (BBB). Two lipoprotein-receptors, LRP-1 and LRP-2, seem to be responsible for efflux of lipoprotein-free or lipoprotein-associated (apoJ-associated) Aß from the brain to blood, respectively [19].
3. Aß is present in either lipoprotein-free or lipoprotein-associated form in brain parenchyma
To assess the above-mentioned issue, we examined whether the dissociation of sAß from lipoprotein-particles occurs in the brain. The combination of size exclusion chromatography (SEC) and enzyme-linked immunosorbent assay (ELISA) revealed that the dissociation of sAß from lipoprotein-particles occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Aß in AD brains [8]. These findings may support the hypothesis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of soluble dimeric SDS-resistant form of Aβ in AD brains [8, 26]. At this moment, it remains undetermined whether dissociation of Aβ from lipoprotein or less association of Aβ to lipoproteins accounts for such a metabolic conditions. To further verify this hypothesis, we focused on the entorhinal cortex (EC), followed by biochemical analyses using an anti-oligomer specific antibody, namely 2C3 [9, 27]. Fifty brains obtained from healthy elderly are composed of three Braak NFT stages; Braak NFT stages I-II (n=35, normal control); Braak NFT stages III-IV (n=13, MCI stage); Braak NFT stages IV-V (n=2, AD stages). Immunoblot analysis of the delipidated EC employing monoclonal 2C3 revealed that the accumulation of soluble 12-mers precedes the appearance of neuronal loss or cognitive impairment, and is enhanced as the Braak neurofibrially tangle (NFT) stages progress, indicating that the ECs of AD patients indeed bear metabolic conditions that accelerate Aβ assembly.
4. Aß is present in either lipoprotein-free or lipoprotein-associated form in cerebrospinal fluid (CSF)9
The presence of lipoprotein-free sAβOs in CSF was also assessed in age-matched normal controls (NCs) and patients with Alzheimer’s disease (AD) by SEC and ELISA specific for either AβOs or AβMs. The SEC experiment using pooled CSF revealed that the dissociation of sAβMs from lipoprotein particles indeed occurs in CSF, which was lower in AD than in NCs. Furthermore, the SEC experiment using lipoprotein-depleted pooled CSF (LPD-CSF) confirmed the presence of oligomeric 2C3 conformers (4- to 35-mers), which appeared to be higher in AD patients than in NCs. To address the issue on the presence of any metabolic conditions favoring Aβ assembly, we compared the levels of lipoprotein-free sAβMs and sAβOs in LPD-CSF from the 12 sporadic AD patients and 13 NCs to evaluate the AβOs/ AβMs ratio (the O/M index). The levels of 2C3 oligomeric conformers composed of Aβ42 are significantly higher in AD patients than in NCs. The O/M index for either Aβ42 or Aβ40 is also significantly higher in AD patients than in NCs. Of note, the relative amounts of total lipoprotein-associated sAβMs (~70%) versus lipoprotein-free sAβMs (~30%) remained essentially unchanged in sporadic AD patients as compared with NCs. However, the relative amounts of lipoprotein-free Aβ42 was significantly lower in the sporadic AD patients (9.3 ± 3.9 %) than in NCs (13.2 ± 4.5 %), which is in accordance with our above-mentioned finding that the level of oligomeric 2C3 conformers composed of Aβ42 was significantly elevated in AD patients. Thus, it is likely that the conversion of lipoprotein-free monomeric soluble Aβ42 into oligomeric assembly preferentially occurs in AD CSF, mirroring the disease-related metabolic conditions in the brain parenchyma.
5. Summary
We previously reported that ~90% of sAβMs that circulate in normal plasma is associated with lipoprotein particles [27]. From the above data, it is plausible to assume that about 70% of CSF sAβMs is normally associated with lipoprotein particles, indicating that CNS constitutes a risky environment where the lipoproteins-sAβMs interaction is impaired, leading to Aβ assembly. From this point of view, a key molecule to maintain monomeric sAβ42 metabolism in CNS appears to be HDL-like lipoprotein particles. In this sense, the dissociation of sAβ42 from or the lack of association with HDL-like lipoprotein particles not only constitutes a potential mechanism to initiate and/or accelerate the cascade favoring Aβ42 assembly in the brain, but also results in a reduced clearance of physiological lipoprotein-associated sAβ42 peptides in the brain. Thus, above-mentioned CNS environments may strongly affect conformation of sAβ peptides, resulting in the conversion of sAβ42 monomers into sAβ42 assembly. The findings suggest that functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of sAβ42 assembly in the CNS.
References
- 1.
Trends Pharmacol SciHardy J. Allsop D. Amyloid deposition. as the central. event in. the aetiology. of Alzheimer’s. disease 1991 - 2.
Am J PatholLue L. F. Kuo Y. M. Roher A. E. Brachova L. Shen Y. Sue L. Beach T. Kurth J. H. Rydel R. E. Rogers J. Soluble amyloid. β. peptide concentration. as predictor a. of synaptic. change in. Alzheimer’s disease. 1999 - 3.
Ann NeurolCA Mc Lean Cherny. R. A. Fraser F. W. Fuller S. J. MJ Smith Beyreuther. K. Bush A. I. Masters C. L. Soluble pool. of Abeta. as amyloid a. determinant of. severity of. neurodegeneration in. Alzheimer’s disease. 1999 - 4.
Klein WL, Krafft GA, Finch CE: Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 2001 - 5.
Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science2002 - 6.
Nat Rev Mol Cell BiolHass C. Selkoe D. J. Soluble protein. oligomers in. neurodegeneration lessons. from the. Alzheimer’s amyloid. β-peptide 2007 - 7.
Neurobiol AgingAkiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G. M. Cooper N. R. Eikelenboom P. Emmerling M. Fiebich B. L. CE Finch Frautschy. S. Griffin W. S. Hampel H. Hull M. Landreth G. Lue L. Mrak R. Mackenzie I. R. Mc Geer P. L. O’Banion M. K. Pachter J. Pasinetti G. Plata-Salaman C. Rogers J. Rydel R. Shen Y. Streit W. Strohmeyer R. Tooyoma I. Van Muiswinkel F. L. Veerhuis R. Walker D. Webster S. Wegrzyniak B. Wenk G. Wyss-Coray T. Inflammation Alzheimer’s disease. 2000 - 8.
Matsubara E. Sekijima Y. Tokuda T. Urakami K. Amari M. Shizuka-Ikeda M. Tomidokoro Y. Ikeda M. Kawarabayashi T. Harigaya Y. Ikeda S. Murakami T. Abe K. Otomo E. Hirai S. Frangione B. Ghiso J. Shoji M. 2004 Soluble Abeta homeostasis in AD and DS: impairment of anti-amyloidogenic protection by lipoproteins. Neurobiol Aging25 833 841 - 9.
The Dissociation of Aβ from Lipoprotein in Cerebrospinal Fluid from Alzheimer’s Disease accelerates Aβ42 assembly. J Neurosci Res.Takamura A. Kawarabayashi T. Yokoseki T. Shibata M. Morishima-Kawashima M. Saito Y. Murayama S. Ihara Y. Abe K. Shoji M. Michikawa M. Matsubara E. 2011 815 821 - 10.
Michikawa M. Gong J. S. Fan Q. W. Sawamura N. Yanagisawa K. 2001 A novel action of alzheimer’s amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J Neurosci21 7226 7235 - 11.
Gong J. S. Sawamura N. Zou K. Sakai J. Yanagisawa K. Michikawa M. 2002 Amyloid beta-protein affects cholesterol metabolism in cultured neurons: implications for pivotal role of cholesterol in the amyloid cascade. J Neurosci Res70 438 46 - 12.
Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem Int.De Mattos R. B. Brendza R. P. Heuser J. E. Kierson M. Cirrito J. R. Fryer J. Sullivan P. M. Fagan A. M. Han X. Holtzman D. M. 2001 5 6 - 13.
The cerebrospinal-fluid soluble form of Alzheimer’s amyloid ß is complexed to SP-40,40 (apolipoprotein J), an inhbitor of the complement membrane-attack complex. Biochem J.,Ghiso J. Matsubara E. Koudinov A. Choi-Miura N. H. Tomita M. Wisniewski T. Frangione B. 1993 293 27 30 - 14.
Biochem Biophys Res Commun.,Wisniewski T. Golabek A. Matsubara E. Ghiso J. Frangione B. Apolipoprotein E. binding to. soluble Alzheimer’s. ß-amyloid 1993 192 359 365 - 15.
The soluble form of Alzheimer’s amyloid ß protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma. Biochem Biophys Res Commun.,Koudinov A. Matsubara E. Frangione B. Ghiso J. 1994 205 1164 1171 - 16.
Characterization of apolipoprotein J-Alzheimer’s A beta interaction. J Biol Chem.Matsubara E. Frangione B. Ghiso J. 1995 - 17.
Biochem J,Matsubara E. Soto C. Governale S. Frangione B. Ghisom J. Apolipoprotein J. Alzheimer’s amyloid. ß. solubility 1996 316 671 679 - 18.
DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295: 2264-2267,2002 - 19.
Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab.Bell R. D. Sagare A. P. Friedman A. E. Bedi G. S. Holtzman D. M. Deane R. Zlokovic B. V. 27 2007 909 918 - 20.
Clearance of Alzheimer’s amyloid-ss[Shibata M. Yamada S. Kumar S. R. Calero M. Bading J. Frangione B. Holtzman D. M. CA Miller Strickland. D. K. Ghiso J. Zlokovic B. V. 1 40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest.2000 Dec;106[12]:1489-99. - 21.
The putative blood-brain barrier transporter for the beta-amyloid binding protein apolipoprotein J is saturated at physiological concentration. Life SciShayo M. RN Mc Lay Kastin. A. J. Banks W. A. 60 1997 115 118 - 22.
J Clin Invest.Deane R. Sagare A. Hamm K. Parisi M. Lane S. Finn M. B. Holtzman D. M. Zlokovic B. V. apo E. isoform-specific disruption. of amyloid. beta peptide. clearance from. mouse brain. 2008 Dec;118[12]:4002 13 - 23.
Zou K. Gong J. S. Yanagisawa K. Michikawa M. 2002 A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci22 4833 4841 - 24.
Wahrle S. E. Jiang H. Parsadanian M. Hartman R. E. Bales K. R. Paul S. M. Holtzman D. M. 2005 Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem280 43236 43242 - 25.
Wahrle S. E. Jiang H. Parsadanian M. Kim J. Li A. Knoten A. Jain S. Hirsch-Reinshagen V. Wellington C. L. Bales K. R. Paul S. M. Holtzman D. M. 2008 Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest118 671 682 - 26.
Matsubara E. Ghiso J. Frangione B. Amari M. Tomidokoro Y. Ikeda Y. Harigaya Y. Okamoto K. Shoji M. 1999 Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer’s disease and Down’s syndrome.Ann Neurol45 537 541 - 27.
Extracellular and Intraneuronal HMW-AbetaOs Represent a Molecular Basis of Memory Loss in Alzheimer’s Disease Model Mouse. Mol Neurodegener.Takamura A. Okamoto Y. Kawarabayashi T. Yokoseki T. Shibata M. Mouri A. Nabeshima T. Sun H. Abe K. Shoji M. Yanagisawa K. Michikawa M. Matsubara E. 2011