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Neural Basis of Hyposmia in Alzheimer’s Disease

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Daniel Saiz-Sánchez, Carlos de la Rosa-Prieto, Isabel Úbeda-Bañón and Alino Martínez-Marcos

Submitted: October 26th, 2010 Published: September 6th, 2011

DOI: 10.5772/18169

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At the beginning of twenty century Alois Alzheimer described the pathology that now bears his name (Alzheimer, 1907). Over a hundred years later, Alzheimer’s disease (AD) is the most common cause of dementia in developed countries. Here eighteen million people are currently affected and the number of patients is expected to increase dramatically with the ongoing increase in the elderly population (Fotuhi et al., 2009, Mount & Downton, 2006). Because no suitable biomarkers are available, the diagnosis of AD remains inconclusive until postmortem pathological analysis, and physicians rely on behavioral manifestations to differentiate between AD and other conditions. For this reason firm diagnosis is generally only made at later stages of the disorder when treatment is purely palliative. These features make AD a social and economic challenge in developed countries (Wimo et al., 2010).

Clinically, AD is characterized by progressive loss of cognitive functions with specific deficits in episodic memory. Clinical diagnosis of is generally only made when cognitive deficits are sufficiently severe to cause dependent status of the patient (Nestor et al., 2004). Pathological analyses of AD brain have described two distinct types of proteinopathy in the frontal and temporal lobes involving the limbic system and the basal forebrain. The first type comprises aggregates of beta-amyloid peptide (Aβ) – a specific fragment of the amyloid precursor protein (APP), a plasma membrane protein. These aggregates accumulate in the extracellular space and give rise to senile plaques (SPs). SPs cause synaptotoxicity, neurotoxicity, oxidative stress and hypoxia (Peers et al., 2009, Selkoe, 2001, 2008). The second proteinopathy occurs in the cytosol. Hyperphosphorylation and abnormal aggregation of the microtubule-associated protein tau leads to the intracellular formation of neurofibrillary tangles (NFTs) which cause cytoskeleton destabilization and eventually cell death (Hernandez & Avila, 2008, Selkoe, 2001).

It has been widely reported that olfactory loss (anosmia and hyposmia) takes place in the early stages of AD, and before any detectable cognitive deficits are present. Interestingly, AD pathology extends throughout the limbic system and the basal forebrain, including the olfactory system (Braak & Braak, 1991). The human olfactory system includes peripheral sensory neurons in the olfactory epithelium; these send their axons across the cribriform plate of the etmoides bone to the olfactory bulbs. In the glomerular layer of the olfactory bulbs their axons synapse with dendrites of the mitral and tufted cells which in turn project to the main olfactory cortex in the basal forebrain. The human olfactory system constitutes complex circuit connections including primary and secondary cortical areas that are connected, as represented schematically in Figure 1.

Figure 1.

Schematic diagram of the human olfactory system. GL, glomerular layer; Mi, mitral cell; PAC, periamygdaloid complex; Pg, periglomerular cell.

The progression of AD pathology has been divided into six stages according to the extent of NFT accumulation. Accumulation is first detected in the entorhinal cortex and hippocampus of the limbic system; this extends into the basal forebrain including the olfactory system (Braak & Braak, 1991, Price et al., 1991, Van Hoesen et al., 1991), and from the rostral entorhinal cortex, periamygdaloid cortex, and piriform cortex, to the olfactory tubercle, anterior olfactory nucleus and olfactory bulbs (Fig. 1). Tau pathology has also been described in the olfactory epithelium (Lee et al., 1993). Olfaction is affected in many psychiatric disorders in addition to AD, including Parkinson’s disease, Huntington’s disease, schizophrenia, senile dementia of Lewy body type, and depression (Atanasova et al., 2008,Kovacs, 2004). It has been widely reported over the past 25 years that olfaction is impaired in AD (Djordjevic et al., 2008, Doty et al., 1987, Mesholam et al., 1998, Murphy, 1999, Murphy et al., 1990, Serby et al., 1985, 1991), and olfaction has become a priority area in the search for biomarkers to establish an early diagnosis of AD and to facilitate early therapeutic intervention (Doty, 2003,Hampel et al., 2010,Hawkes, 2009,Wilson et al., 2009). It has been proposed that the early involvement of the entorhinal cortex and the hippocampus, regions that are tightly related to memory deficiencies (Nagy et al., 1996), could be also the cause of olfactory deficits (Wilson et al., 2007). However, other authors suggest that alternative olfactory areas, for example the posterior part of the piriform cortex, are the specific cause of olfactory deficiencies (Li et al., 2010). Nevertheless, the neural basis underlying hyposmia in the AD brain remain uncertain.


2. Materials and methods

We have studied the olfactory system in 19 AD cases and 7 age-matched controls from the Banc de Teixits Neurològics, Universitat de Barcelona-Hospital Clínic and the Banco de Tejidos/Fundación para Investigaciones Neurológicas, Universidad Complutense de Madrid. Mean ages (± standard derivation) in AD and controls were 77.68 ± 9.01 yr and 74.57 ± 4.47 yr, respectively.Tissue samples were fixed by immersion in paraformaldehyde 4% for one month at least. Then, samples were cryoprotected in 30% w/v sucrose and 50µm coronal sections were obtained using a sliding freezing microtome.

To study the early stages of disease development we employed a double transgenic mouse model of Alzheimer disease (Appswe/Psen1Δ9). Animals at 2, 4, 6 to 8 months of age (n = 4 homozygous and 4 control female mice per group; N = 32) were collected for analysis.Animals were anesthetized with a mixture of ketamine hydrochloride (Ketolar, Parke-Davis, Madrid, Spain, 1.5 ml/kg, 75 mg/kg) and xylazine (Xilagesic, Calier, Barcelona, Spain, 0.5 ml/kg, 10 mg/kg). Mice were transcardially perfused with saline solution followed by 4% w/v paraformaldehyde fixative (phosphate buffered; 0.1 M, ph 7.2). Brains were removed from skulls and cryoprotected in 30% w/v sucrose, and sectioned (50 µm) in the frontal plane (brains) or in the sagittal plane (olfactory bulbs) using a sliding freezing microtome.

In order to delimit areas of interest sections were stained by Nissl technique (Fig. 2A). Primaryantibodies used for immunodetection were mouse anti-tau (tau 46,1:800, Cell Signaling Technology, Beverly, MA, USA), rabbit anti-Aβ(1:250, Cell Signaling Technology), and goat anti-somatostatin D-20(1:1000, Santa Cruz Biotechnology, Santa Cruz, CA, USA). Secondaryantibodies were either biotinylated (anti-goat IgG, 1:2000, VectorLaboratories, Burlingame, CA, USA) or fluorescent-labeled (1:200,alexas 488 donkey anti-mouse, 568 donkey anti-rabbit, and 350donkey anti-goat; Molecular Probes, Invitrogen, Carlsbad, CA, USA).

For quantification, somatostatin-positive cells were charted with an X-Y recording system (AccuStage, Minnesota Datametrics, MN, USA). Colocalization levels were measured by confocal microscopy using LSM 710 Zeiss confocalmicroscope (Carl Zeiss MicroImaging, Barcelona, Spain).Intensities of each fluorochrome were analyzed using the profiletool of the ZEN software (Zeiss).

One-way ANOVA followed by post hoc Bonferroni test (p<0.05) was used to estimate significant differences among markers and age groups.


3. Interneurons in the olfactory system

Interneurons constitute 20–30% of the neuronal population of the cerebral cortex and possess distinct morphological, electrophysiological and neurochemical characteristics (Ascoli et al., 2008, DeFelipe, 1997, Markram et al., 2004). Two primary features are common to all interneuron subpopulations. First, these cells are predominantly inhibitory interneurons which express γ-aminobutyric acid (GABA), an inhibitory neurotransmitter; and, second, their neuronal connectivity is predominantly restricted to the local region of the brain (DeFelipe & Farinas, 1992, Kawaguchi & Kondo, 2002).

Interneurons are tightly related to the pathoetiology of AD, and many reports have described the involvement of interneuron subpopulations in AD neuropathology (Attems et al., 2008, Brady & Mufson, 1997, Geula et al., 2003, Saiz-Sanchez et al., 2010, Solodkin et al., 1996, Supnet & Bezprozvanny). It was recently reported that numbers of interneurons in the entorhinal cortex and hippocampus are significantly reduced in early AD stages (Koliatsos et al., 2006). Interneurons regulate synaptic signaling by pyramidal neurons and the loss of this regulation could produce deficits in learning and memory (Palop et al., 2003, Wallenstein & Hasselmo, 1997). Moreover, disregulation of olfactory information-processing due to loss of interneurons could underlie the hyposmia described in the early stages of the disease. This review focuses on four major types of interneurons based on their importance to AD etiology and brain calcium homeostasis: respectively cells expressing somatostatin, calbindin, calretinin or parvalbumin. We also discuss the distribution of different types of interneurons and their involvement with tau and β-amyloid pathology as revealed by confocal microscopy.

3.1. Somatostatin

The neuropeptide somatostatin is implicated in diverse functions in the central nervous system (Epelbaum, 1986,Viollet et al., 2008). Somatostatin is expressed in all olfactory areas. Recently, somatostatin has been linked with AD etiology because it is reported to act as a positive regulator of neprilysin, an enzyme which catalyzes the degradation of β-amyloid peptide (Saito et al., 2005). Somatostatin levels decline with aging (Lu et al., 2004) and are further reduced in AD (Davies et al., 1980). It has been proposed that the decline in somatostatin levels with age could explain the age-dependency of AD onset because reduced somatostatin would be expected to lead to downregulation of neprilysin activity, thereby predisposing to the accumulation of β-amyloid peptide (Hama & Saido, 2005).

Confocal microscopy of the olfactory system in AD brain has revealed that somatostatin is selectively reduced, by up to 50%, in olfactory areas such as anterior olfactory nucleus (AON). Moreover, the deficiency in somatostatin was predominantly associated with β-amyloid pathology rather than tau pathology (Figs 2,3). These findings are in agreement with the theory of Hama & Saido that there is a tight relationship between somatostatin and β-amyloid. The AON is an important relay in olfactory information processing (Price, 1990). Two distinct portions of the AON can be distinguished in the basal forebrain – the medial AON and the lateral AON divided by the olfactory tract (Fig. 2A). The AON is an early site for the accumulation of tau protein (Fig. 2B) (Price et al., 1991) and is also targeted for β-amyloid deposition (Fig. 2C). Somatostatin-expressing cells in the AON possess typical bipolar interneuron morphology. Confocal analyses show that most somatostatin-cells expressing are not associated with tau pathology (Figs 2E,Fand 3), and somatostatin-expressing cells are most commonly associated with β-amyloid or with β-amyloid plus tau (Figs 2F and 3).

In Appswe/Psen1Δ9 mice, somatostatin is expressed in all olfactory areas. Expression levels decline with age, and are most markedly reduced in the areas where AD initiates, for example the entorhinal cortex. As in the human AD brain, confocal analyses of the olfactory system of double transgenic mice revealed a correlation between somatostatin expression and β-amyloid pathology. Colocalization with β-amyloid peptide was very extensive and was evident in the youngest animals analyzed. Colocalization was seen in all olfactory areas with the exception of the olfactory bulb. Notably, colocalization of somatostatin-expressing interneurons with β-amyloid peptide was evident (Figs 4, 5), even in the absence of reduced levels of somatostatin expression.

Figure 2.

Expressionof somatostatin, tau and β-amyloid in the anterior olfactory nucleus (AON) in Alzheimer’s disease. (A) Nissl staining of AON in the basal forebrain. (B) Immunohistochemistry of tau protein (blue arrow, dystrophic neuron; blue arrowhead, cellular debris). (C) β-Amyloid positive senile plaques in AON. (D) Somatostatin-expressing cell in the AON showing a dystrophic neuron (black arrow). (E) Double immunofluorescence for somatostatin (green) and tau protein (red). Confocal image of triple immunofluorescence for somatostatin (blue), β-amyloid (red) and tau (green). Note aneuron positive only for tau protein (white arrowhead) and a typical senile plaque (red). Scale bar: A = 400 µm, B & F = 80 µm, D, C & E = 40 µm.

Figure 3.

Percentage of the three different types of colocalization of somatostatin-expressing cells (SOM) with tau protein (tau) and β-amyloid peptide (Aβ) in the human anterior olfactory nucleus.

Figure 4.

Percentages of somatostatin and β-amyloid colocalization in the APPswe/PSEN1Δ9 mice olfactory system. Note that the external plexiform layer from the olfactory bulb is absent. AON, anterior olfactory nucleus; LEnt, lateral entorhinal cortex; Pir, piriform cortex; Tu, olfactory tubercle.

All olfactory areas showed a marked accumulation of β-amyloid deposits, but the extent of accumulation in olfactory tubercle (Tu) was less than in other areas (Fig. 5 A–D). The greatest reduction in cells expressing somatostatin was seen in the external plexiform layer (EPL) (Fig. 5E,F) of the olfactory bulb, the piriform cortex (Pir) and the entorhinal cortex (Ent). In addition, the olfactory tubercle (Tu) and anterior olfactory nucleus (AON) both showed

significant reductions in levels of somatostatin-positive cells. Different forms of colocalization were observed,including isolated cells (Fig. 5G), fibers and cell debris (Fig. 5H,I). Colocalization increased with age and was greater in caudal olfactory areas than in rostral areas. No colocalization was found in the external plexiform layer of the olfactory bulb where β-amyloid pathology was restricted to the granule cell layer (Fig. 5A,D) and was largely absent from the EPL.

Figure 5.

Somatostatin and β-amyloid in the olfactory system of APPswe/PSEN1Δ9 mice. Green, β-amyloid; red, somatostatin. Immunohistochemistry for β-amyloid in the olfactory bulb (A), including anterior olfactory nucleus, piriform cortex and olfactory tubercle (B) and entorhinal cortex (C). Immunofluorescence in the olfactory bulb for β-amyloid (D) and somatostatin in a control mouse (E) and 6 months old transgenic mice (F). Confocal images demonstrating β-amyloid colocalization with somatostatin-expressing cells (G), fibers and cell debris (H, I). Scale bar: A, B, C & D = 400 µm, E & F = 80 µm, G & H = 40 µm, I = 25 µm

3.2. Calcium-binding proteins

Calcium is an intracellular second messenger that mediates physiological responses of neurons to chemical and electrical stimulation. In AD defective calcium homeostasis is thought to cause aberrant cellular metabolism and promote cell death (Heizmann & Braun, 1992,Mattson, 2007). Calcium has been related to changes in learning (Foster, 2007,Palop et al., 2003) and altered calcium regulation has been reported in AD brains before any cognitive deficits become apparent (Bezprozvanny & Mattson, 2008).

Our analysis focused on three interneuron subpopulations expressing three different calcium-binding proteins (CaBP): calbindin, calretinin and parvalbumin. All three proteins are expressed in the olfactory system, but with different distributions.

3.3. Calbindin

Most studies on calbindin D-28k have concluded that there is a general decline in levels in AD brain compared to controls (Ferrer et al., 1993,Iacopino & Christakos, 1990,Ichimiya et al., 1988).

In AD brain, calbindin D-28k is expressed widely throughout the olfactory system and is particularly abundant in key structures of olfactory processing such as the AON (Fig. 6A,B) and the piriform cortex (Fig. 6C). Especially evident is the pathological involvement of calbindin 28-Dk in the piriform cortex (Fig. 6C) where aberrant morphologies of calbindin-expressing dystrophic neuritis can be observed (Fig. 6D). Although calbindin-positive cells in the human olfactory system show some involvement with β-amyloid pathology, there was a stronger association with tau pathology (Fig. 6E,F).

Figure 6.

Calbindin D-28k in the olfactory system of Alzheimer’s disease brain. Green, tau protein and red, calbindin D-28k. (A) Nissl staining of the human anterior olfactory nucleus (AON). (B) Calbindin- expressing cell in the AON. (C) Calbindin- expressing cell in the piriform cortex (Pir). (D) Detail of a dystrophic neurite. (E) Tau pathology in Pir. (F) Calbindin-expressing cell with associated tau pathology. Scale bar: A = 160 µm, B & C = 80 µm, E = 40 µm, D & F = 25 µm.

3.4. Calretinin

Whereas calbindin D-28k is firmly associated with AD neuropathology, the involvement of calretinin in AD is more controversial (Brion & Resibois, 1994,Fonseca & Soriano, 1995,Hof et al., 1993,Sampson et al., 1997). Some authors propose that calretinin-positive cells are resistant to disease progression as a result of its capacity to buffer intracellular calcium levels. Furthermore, the potential role of calretinin in the neural basis of hyposmia remains unclear. We have studied the distribution of calretinin distribution in the human olfactory system and its involvement by tau and β-amyloid pathology.

Microscopy observations revealed that calretinin is present throughout the olfactory system. AD brain expression levels were found to be markedly reduced in olfactory areas such as AON (Fig. 7B) and Pir (Fig. 7C) relative to control brain (Fig. 7D). As with calbindin-expressing cells, calretinin-positive cells showed aberrant morphologies. In addition, these cells showed preferential involvement of tau pathology. In the olfactory bulb calretinin was found to be expressed in the periglomerular cells (Fig. 7A). It is interesting to note that sensory neurons from the olfactory epithelium send their axons to glomeruli in the olfactory bulb where they make synapses with dendrites of mitral cells. These synapses are regulated by periglomerular cells (Fig. 1). Involvement of periglomerular cells could therefore lead to disregulation of olfactory perception at the early stages of the disease.

Figure 7.

Calretinin-expressing cells in the human olfactory system. (A) Periglomerular cells in the glomerular layer (GL) in the human olfactory bulb. (B) Calretinin-expressing cells in the anterior olfactory nucleus (AON). Expression of calretinin in (C) control and (D) Alzheimer’s disease piriform cortex (Pir). Scale bar: A & B = 80 µm, C & D = 400 µm.

3.5. Parvalbumin

The third subclass of interneurons studied were those expressing parvalbumin. As with calretinin, the involvement of parvalbumin in AD is controversial. On the one hand it has been reported that there is an up to 60% decrease in the parvalbumin-positive cell population in AD hippocampus (Brady & Mufson, 1997) and entorhinal cortex (Mikkonen et al., 1999,Solodkin et al., 1996). On the other, no association was found between parvalbumin-positive cells and tau pathology in AD (Sampson et al., 1997).

In the human brain parvalbumin-expressing cells were present throughout the olfactory system and were particularly abundant in caudal olfactory areas such as piriform cortex (Fig. 8) and entorhinal cortex. In contrast to cells expressing calbindin- and calretinin, parvalbumin-positive cells showed physiological morphology, even at advanced stages of disease (Fig. 8A,B). Confocal images showed that parvalbumin-positive cells were predominantly associated with tau pathology (Fig. 8C); there was less evidence of involvement with β-amyloid pathology. As with calbindin- and calretinin-expressing cells, tau/NFT was the predominantly neuropathology associated with these calcium-binding proteins.

Figure 8.

Parvalbumin-expressing cells in the human olfactory system. Green, tau protein and red, parvalbumin. Immunohistochemistry of Alzheimer (A) and control (B) brain piriform cortex (Pir). (C) Confocal image of the Pir demonstrating the association of parvalbumin-expressing cells with tau pathology. Scale bar: A & B = 80 µm, C = 25 µm.


4. Discussion

In the present report we have studied the involvement of interneuron populations in the human olfactory system with AD neuropathology as revealed by two different disease markers: tau protein and β-amyloid peptide. Somatostatin-expressing interneurons in the olfactory system were preferentially associated with β-amyloid pathology in both AD brain and in Appswe/Psen1Δ9 mice. By contrast, interneurons expressing different calcium-binding proteins were predominantly associated with tau pathology. In transgenic mice, cells expressingSomatostatin-cell expressing was colocalized with β-amyloid pathology in the youngest animals examined, with the exception of the external plexiform layer, and the colocalization was evident even before disease-related reduction in the numbers of somatostatin cells.

The four subpopulations of interneurons were not randomly distributed within the olfactory system. Somatostatin-expressing cells were present in the olfactory bulb but were restricted to the external plexiform layer (EPL) (Fig. 5). Somatostatin was also present in other olfactory areas, particularly in the anterior olfactory nucleus (AON). Calbindin-expressing cells were present in the olfactory system, and were particularly abundant in the AON. Calretinin-positivity constitutes a specific marker for periglomerular cells which regulate the first relay of olfactory information from the olfactory epithelium to the olfactory bulbs (Fig. 1). Calretinin-expressing cells were also abundant in the piriform cortex (Pir) and the entorhinal cortex (Ent). Parvalbumin-positive cells were more abundant in the more caudal areas studied (Pir and Ent) and were only sparsely distributed in rostral olfactory areas.

The wide presence of these interneuron populations in olfactory structures and the severe and early involvement of these regions in AD neuropathology has focused attention on the role of these cells in the pathoetiology of AD. Generalized involvement of these cells and loss of interneuron populations and/or disregulation of their primary projection cellscould underlie the olfactory deficits of AD patients. Loss of inhibitory regulation by γ-aminobutyric acid (GABA) could lead to altered firing patterns of projection neurons.

The olfactory system encompasses complex interconnections between several cortical areas (Fig. 1). Although it remains unknown whether dysfunction of specific interneuron populations in any given area could cause the olfaction deficits seen in AD, we report that there was selective association between different types of interneuron and AD neuropathology, as revealed by the two pathological markers employed in this study. However, it is not yet possible to relate these changes with specific olfaction deficits such as preferential or general anosmia, hyposmia or dysosmia. The specific contribution of each area in olfactory processing and how they are differentially affected during AD will need to be resolved before a specific olfactory test can be devised that could permit early diagnosis of AD.



The authors thank the Banc de Teixits Neurològics, Universitat de Barcelona-Hospital Clínic and the Banco de Tejidos/Fundación para Investigaciones Neurológicas, Universidad Complutense de Madrid, for providing the human brain samples. The authors also wish to thank the laboratory of Dr. Calvo for genotyping transgenic mice. This work was supported by the autonomous government of Castilla-La Macha (Project Nº PEIC11-0045-4490) and by the Spanish Science and Innovation Ministry (Project BFU2010-15729).


  1. 1. AscoliG. A.Alonso-NanclaresL.AndersonS. A.BarrionuevoG.Benavides-PiccioneR.BurkhalterA.BuzsakiG.CauliB.DefelipeJ.FairenA.FeldmeyerD.FishellG.FregnacY.FreundT. F.GardnerD.GardnerE. P.GoldbergJ. H.HelmstaedterM.HestrinS.KarubeF.KisvardayZ. F.LambolezB.LewisD. A.MarinO.MarkramH.MunozA.PackerA.PetersenC. C.RocklandK. S.RossierJ.RudyB.SomogyiP.StaigerJ. F.TamasG.ThomsonA. M.Toledo-RodriguezM.WangY.WestD. C.YusteR.2008 Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortexNat Rev Neurosci, 97July 2008), 5575681471-0048
  2. 2. AtanasovaB.GrauxJ.El HageW.HommetC.CamusV.BelzungC.2008 Olfaction: a potential cognitive marker of psychiatric disordersNeurosci Biobehav Rev, 327September 2008), 131513250149-7634
  3. 3. AttemsJ.PreusserM.Grosinger-QuassM.WagnerL.LintnerF.JellingerK.2008 Calcium-binding protein secretagogin-expressing neurones in the human hippocampus are largely resistant to neurodegeneration in Alzheimer’s diseaseNeuropathol Appl Neurobiol, 341February 2008), 23320305-1846
  4. 4. BezprozvannyI.MattsonM. P.2008 Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci, 319September 2008), 4544630166-2236
  5. 5. BraakH.BraakE.1991 Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol, 8242392590001-6322
  6. 6. BradyD. R.MufsonE. J.1997 Parvalbumin-immunoreactive neurons in the hippocampal formation of Alzheimer’s diseased brain. Neuroscience, 804October 1997), 111311250306-4522
  7. 7. BrionJ. P.ResiboisA.1994 A subset of calretinin-positive neurons are abnormal in Alzheimer’s disease.Acta Neuropathol, 88133430001-6322
  8. 8. DaviesP.KatzmanR.TerryR. D.1980 Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa.Nature2885788November 1980), 2792800028-0836
  9. 9. De FelipeJ.1997 Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. J Chem Neuroanat, 141December 1997), 1190891-0618
  10. 10. De FelipeJ.FarinasI.1992 The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs.Prog Neurobiol, 396December 1992), 5636070301-0082
  11. 11. DjordjevicJ.Jones-GotmanM.De SousaK.ChertkowH.2008 Olfaction in patients with mild cognitive impairment and Alzheimer’s diseaseNeurobiol Aging, 295May 2008), 6937061558-1497
  12. 12. DotyR. L.2003 Handbook of olfaction and gustation. Doty RL, editor; 2003.
  13. 13. DotyR. L.ReyesP. F.GregorT.1987 Presence of both odor identification and detection deficits in Alzheimer’s disease.Brain Res Bull, 185May 1987), 5976000361-9230
  14. 14. EpelbaumJ.1986 Somatostatin in the central nervous system: physiology and pathological modifications.Prog Neurobiol, 271631000301-0082
  15. 15. FerrerI.TunonT.SerranoM. T.CasasR.AlcantaraS.ZujarM. J.RiveraR. M.1993 Calbindin D-28k and parvalbumin immunoreactivity in the frontal cortex in patients with frontal lobe dementia of non-Alzheimer type associated with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry, 563March 1993), 2572610022-3050
  16. 16. FonsecaM.SorianoE.1995 Calretinin-immunoreactive neurons in the normal human temporal cortex and in Alzheimer’s diseaseBrain Res, 6911-2September 1995), 83910006-8993
  17. 17. FosterT. C.2007 Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell, 63June 2007), 3193251474-9718
  18. 18. FotuhiM.HachinskiV.WhitehouseP. J.2009 Changing perspectives regarding late-life dementiaNat Rev Neurol, 512December 2009), 6496581759-4766
  19. 19. GeulaC.BuJ.NagykeryN.ScintoL. F.ChanJ.JosephJ.ParkerR.WuC. K.2003 Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss.J Comp Neurol, 4552January 2003), 2492590021-9967
  20. 20. HamaE.SaidoT. C.2005 Etiology of sporadic Alzheimer’s disease: somatostatin, neprilysin, and amyloid beta peptide.Med Hypotheses, 6534985000306-9877
  21. 21. HampelH.FrankR.BroichK.TeipelS. J.KatzR. G.HardyJ.HerholzK.BokdeA. L.JessenF.HoesslerY. C.SanhaiW. R.ZetterbergH.WoodcockJ.BlennowK.2010 Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives.Nat Rev Drug Discov, 97July 2010), 5605741474-1784
  22. 22. HawkesC. H.DotyR. L. The Neurology of Olfaction: Cambridge University Press,Cambridge; 2009
  23. 23. HeizmannC. W.BraunK.1992 Changes in Ca(2+)-binding proteins in human neurodegenerative disorders. Trends Neurosci, 157July 1992), 2592640166-2236
  24. 24. HernandezF.AvilaJ.2008 Tau aggregates and tau pathology.J Alzheimers Dis, 144August 2008), 4494521387-2877
  25. 25. HofP. R.NimchinskyE. A.CelioM. R.BourasC.MorrisonJ. H.1993 Calretinin-immunoreactive neocortical interneurons are unaffected in Alzheimer’s disease.Neurosci Lett, 1521-2April 1993), 1451480304-3940
  26. 26. IacopinoA. M.ChristakosS.1990 Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases.Proc Natl Acad Sci U S A, 8711January 1990), 407840820027-8424
  27. 27. IchimiyaY.EmsonP. C.MountjoyC. Q.LawsonD. E.HeizmannC. W.1988 Loss of calbindin-28K immunoreactive neurones from the cortex in Alzheimer-type dementia.Brain Res, 4751December 1988), 1561590006-8993
  28. 28. KawaguchiY.KondoS.2002 Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex. J Neurocytol, 313-5March-June 2002), 2772870300-4864
  29. 29. KoliatsosV. E.KecojevicA.TroncosoJ. C.GastardM. C.BennettD. A.SchneiderJ. A.2006 Early involvement of small inhibitory cortical interneurons in Alzheimer’s diseaseActa Neuropathol, 1122August 2006), 1471620001-6322
  30. 30. KovacsT.2004 Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders.Ageing Res Rev, 32April 2004), 2152321568-1637
  31. 31. LeeJ. H.GoedertM.HillW. D.LeeV. M.TrojanowskiJ. Q.1993 Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer patients and developmentally regulated in human fetal spinal cordExp Neurol, 1211May 1993), 931050014-4886
  32. 32. LiW.HowardJ. D.GottfriedJ. A.2010 Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer’s disease. Brain, 1339August 2010), 271427261460-2156
  33. 33. LuT.PanY.KaoS. Y.LiC.KohaneI.ChanJ.YanknerB. A.2004 Gene regulation and DNA damage in the ageing human brain. Nature, 4296994June 2004), 8838911476-4687
  34. 34. MarkramH.Toledo-RodriguezM.WangY.GuptaA.SilberbergG.WuC.2004 Interneurons of the neocortical inhibitory systemNat Rev Neurosci, 510October 2004), 7938070147-1003X
  35. 35. MattsonM. P.2007 Calcium and neurodegeneration. Aging Cell, 63June 2007), 3373501474-9718
  36. 36. MesholamR. I.MobergP. J.MahrR. N.DotyR. L.1998 Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol, 551January 1998), 84900003-9942
  37. 37. MikkonenM.AlafuzoffI.TapiolaT.SoininenH.MiettinenR.1999 Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin-D28K immunoreactivity in the entorhinal cortex in Alzheimer’s disease.Neuroscience9225155320306-4522
  38. 38. MountC.DowntonC.2006 Alzheimer disease: progress or profit? Nat Med, 1277807841078-8956
  39. 39. MurphyC.1999 Loss of olfactory function in dementing disease. Physiol Behav, 662April 1999), 1771820031-9384
  40. 40. MurphyC.MMGilmoreSeery. C. S.SalmonD. P.LaskerB. R.1990 Olfactory thresholds are associated with degree of dementia in Alzheimer’s disease. Neurobiol Aging, 114July-August 1990), 4654690197-4580
  41. 41. NagyZ.JobstK. A.EsiriM. M.MorrisJ. H.KingE. M.MacDonald. B.LitchfieldS.BarnetsonL.SmithA. D.1996 Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer’s disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria. Dementia, 72March-April 1996), 76811013-7424
  42. 42. NestorP. J.ScheltensP.HodgesJ. R.2004 Advances in the early detection of Alzheimer’s disease. Nat Med, 10Suppl, No. (July 2004), S34S411078-8956
  43. 43. PalopJ. J.JonesB.KekoniusL.ChinJ.YuG. Q.RaberJ.MasliahE.MuckeL.2003 Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proc Natl Acad Sci U S A, 10016August 2003), 957295770027-8424
  44. 44. PeersC.DallasM. L.BoycottH. E.ScraggJ. L.PearsonH. A.BoyleJ. P.2009 Hypoxia and neurodegeneration. Ann N Y Acad Sci, 1177No. (October 2009), 1691771749-6632
  45. 45. PriceJ. L.1990 Olfactory System. In: Paxinos G, editor. The Human Nervous System. San Diego: Academic Press; 1990. 979998
  46. 46. PriceJ. L.DavisP. B.MorrisJ. C.WhiteD. L.1991 The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging, 124July-August 1991), 2953120197-4580
  47. 47. SaitoT.IwataN.TsubukiS.TakakiY.TakanoJ.HuangS. M.SuemotoT.HiguchiM.SaidoT. C.2005 Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med, 114April 2005), 4344391078-8956
  48. 48. la Rosa-PrietoC.Argandona-PalaciosL.Garcia-MunozgurenS.InsaustiR.Martinez-MarcosA.2010 Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol, 2232June 2010), 3473501090-2430
  49. 49. SampsonV. L.MorrisonJ. H.VickersJ. C.1997 The cellular basis for the relative resistance of parvalbumin and calretinin immunoreactive neocortical neurons to the pathology of Alzheimer’s disease. Exp Neurol, 1451May 1997), 2953020014-4886
  50. 50. SelkoeD. J.2001 Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev, 812April 2001), 7417660031-9333
  51. 51. SelkoeD. J.2008 Biochemistry and Molecular Biology of Amyloid beta-Protein and the Mechanism of Alzheimer’s Disease. Handb Clin Neurol, 89No. 2452600072-9752
  52. 52. SerbyM.CorwinJ.NovattA.ConradP.RotrosenJ.1985 Olfaction in dementia. J Neurol Neurosurg Psychiatry, 488September 1985), 8488490022-3050
  53. 53. SerbyM.LarsonP.KalksteinD.1991 The nature and course of olfactory deficits in Alzheimer’s disease. Am J Psychiatry, 1483March 1991), 3573600000-2953X
  54. 54. SolodkinA.VeldhuizenS. D.Van HoesenG. W.1996 Contingent vulnerability of entorhinal parvalbumin-containing neurons in Alzheimer’s disease. J Neurosci, 1610May 1996), 331133210270-6474
  55. 55. SupnetC.BezprozvannyI.2010 The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium, 472February 2010) 1831891532-1991
  56. 56. Van HoesenG. W.HymanB. T.DamasioA. R.1991 Entorhinal cortex pathology in Alzheimer’s disease. Hippocampus, 11January 1991), 181050-9631
  57. 57. ViolletC.LepousezG.LoudesC.VideauC.SimonA.EpelbaumJ.2008 Somatostatinergic systems in brain: Networks and functions. Mol Cell Endocrinol, 2861-2May 2008), 75870303-7207
  58. 58. WallensteinG. V.HasselmoM. E.1997 GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect. J Neurophysiol, 781July 1997), 3934080022-3077
  59. 59. WilsonR. S.ArnoldS. E.SchneiderJ. A.BoyleP. A.BuchmanA. S.BennettD. A.2009 Olfactory impairment in presymptomatic Alzheimer’s disease. Ann N Y Acad Sci, 1170No. (July 2009), 7307351749-6632
  60. 60. WilsonR. S.ArnoldS. E.SchneiderJ. A.TangY.BennettD. A.2007 The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry, 781January 2007), 30350146-8330X
  61. 61. WimoA.WinbladB.JonssonL.2010 The worldwide societal costs of dementia: Estimates for 2009. Alzheimers Dement, 62March 2010), 981031552-5279

Written By

Daniel Saiz-Sánchez, Carlos de la Rosa-Prieto, Isabel Úbeda-Bañón and Alino Martínez-Marcos

Submitted: October 26th, 2010 Published: September 6th, 2011