Volume 18, Number 2, October 2009

Pages 243-251
Review Article
Jürgen Götz, Nicole Schonrock, Bryce Vissel, Lars M. Ittner
Alzheimer’s disease selective vulnerability and modelling in transgenic mice
Abstract: Neurodegenerative diseases are characterized by ‘hot spots’ of degeneration. The regions of primary vulnerability vary between different neurodegenerative diseases. Within these regions, some neurons are lost whereas others that are morphologically indiscriminate survive. The enigma of this selective vulnerability is tightly linked to two fundamental problems in the neurosciences. First, it is not understood how many neuronal cell types make up the mammalian brain; estimates are in the order of more than a thousand. Second, the mechanisms by which some nerve cells undergo functional impairment followed by degeneration while others do not, remain elusive. Understanding the basis for this selective vulnerability has significant implications for understanding the pathogenesis of disease and for developing treatments. Here, we review what is known about selective vulnerability in Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease. We suggest, since transgenic animal models of disease reproduce aspects of selective vulnerability, that these models offer a valuable system for future investigations into the physiological basis of selective vulnerability.

Pages 253-265
Review Article
Hidenori Taru, Toshiharu Suzuki
Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins
Abstract: Amyloid-β protein precursor (AβPP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer’s disease. The cytoplasmic domain of AβPP is important for the metabolism and physiological functions of AβPP and contains a GYENPTY motif that interacts with proteins that contain a phosphotyrosine binding (PTB) domain such as X11/Mint, FE65, and the JIP family of proteins. X11 and X11-like proteins are neuronal adaptor proteins involved in presynaptic function and the intracellular trafficking of proteins. Recent studies in X11s knockout mice confirmed findings from in vitro studies that X11 proteins affect AβPP metabolism and the generation of amyloid-β peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of AβPP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with AβPP to play a role in neuronal cytoskeletal regulation. c-Jun N-terminal kinase (JNK) interacting protein-1, a scaffolding protein for the JNK kinase cascade, has been suggested to mediate the intracellular trafficking of AβPP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of AβPP by AβPP binding proteins.

Pages 267-271
Short Communication
Sergio Cammarata, Roberta Borghi, Luca Giliberto, Matteo Pardini, Valeria Pollero, Cristina Novello, Michele Fornaro, Antonella Vitali, Laura Bracco, Carlo Caltagirone, Paola Bossù, Patrizio Odetti, Massimo Tabaton
Amyloid-β42 Plasma Levels are Elevated in Amnestic Mild Cognitive Impairment
Abstract: Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer’s disease (AD). We measured plasma levels of amyloid-β40 (Aβ40) and Aβ42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Aβ42, as well as the Aβ42/Aβ40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Aβ42 and, to a lesser extent, Aβ40 than the stable cases. However the large variability of measured values indicates that plasmatic Aβ is not a suitable marker of incipient AD.

Pages 273-280
Weiqian Mi, Sonia S. Jung, Haung Yu, Stephen D. Schmidt, Ralph A. Nixon, Paul M. Mathews, Fabrizio Tagliavini, Efrat Levy (Communicated by Luciano D’Adamio)
Complexes of Amyloid-β and Cystatin C in the Human Central Nervous System
Abstract: A role for cystatin C (CysC) in the pathogenesis of Alzheimer’s disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-β (Aβ) in AD brains, and binding of CysC to soluble Aβ in vitro and in mouse models of AD. This study investigates the binding between Aβ and CysC in the human central nervous system. While CysC binding to soluble Aβ was observed in AD patients and controls, an SDS-resistant CysC/Aβ complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with Aβ in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Aβ and CysC prevented Aβ accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explain why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to Aβ have important disease modifying effects, suggesting a novel therapeutic intervention for AD.

Pages 281-293
Leticia Ramírez-Lugo, Morten S. Jensen, Andreas Søderman and Mark J. West
Deficits in Aversive but not in Safe Taste Memory in the APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease
Abstract: Age-related changes in taste memory were evaluated in APPswe/PS1dE9 transgenic (Tg) mice and age matched wild type littermate controls (Wt). These Tg mice produce increasing amounts of amyloid-β in the brain with age, develop significant amounts of plaques by 9 months of age, and provide an opportunity to study the effects of Alzheimer’s disease-like amyloidosis on different aspects of taste memory. In groups of mice ranging from 15-16 months of age, the neophobic response and its attenuation were similar in Tg and Wt mice. However, conditioned taste aversion (CTA), which resulted from the association between a new taste and an artificially induced gastric malaise, was significantly reduced in the 15-16 month old Tg mice compared to the Wt mice, but not in the 3-4 or 7-8 month old mice. The extinction of CTA was normal in 3-4 month old Tg mice, but occurred more rapidly in the 7-8 and 15-16 months old Tg mice than in the age-matched controls. These results provide evidence of differences in the neuronal systems involved in the attenuation of neophobia and CTA and suggest that the progressive amyloidosis that takes place in APPswe/PS1dE9 mice selectively affects the aversion component of taste memory.

Pages 295-303
Roberta Ghidoni, Valentina Albertini, Rosanna Squitti, Anna Paterlini, Anna Bruno, Silvia Bernardini, Emanuele Cassetta, Paolo Maria Rossini, Ferdinando Squitieri, Luisa Benussi, Giuliano Binetti
Novel T719P AβPP Mutation Unbalances the Relative Proportion of Amyloid-β Peptides
Abstract: A novel missense mutation (T719P) in the amyloid-β protein precursor (AβPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer’s disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-β peptides (Aβ) in cerebrospinal fluid (CSF) of the AβPP mutated patient, healthy control subjects (n=10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Aβ peptides were found in CSF. The investigated AβPP as well as PS mutations were associated with an overall reduction of Aβ species, except for Aβ10-40. Interestingly, the AβPP T719P mutation unbalanced the relative proportion of Aβ peptides with a reduction of Aβ1-40 and Aβ1-42 paralleled by an increase of Aβ1-38 and Aβ10-40. Despite the specific neuropeptidomic phenotype associated with the AβPP T719P mutation, the enrichment in Aβ10–40 paralleled by depletion of Aβ1–42 seems to be a common theme in familial AD. The AβPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AβPP ε-cleavage site.

Pages 305-317
Mengqi Chen, Ralph N. Martins, Michael Lardelli
Complex Splicing and Neural Expression of Duplicated Tau Genes in Zebrafish Embryos
Abstract: Microtubule-associated protein tau (MAPT) is the major component of the neurofibrillary tangles found in the brains of those suffering from Alzheimer’s disease. Various forms of tau lesions are found in other neurodegenerative diseases (tauopathies). We report identification of two MAPT paralogous genes in zebrafish, mapta and maptb, and analysis of their expression patterns during embryonic development. The two paralogues appear to have arisen by duplication of an ancestral teleost MAPT orthologue. Analysis of the splicing of transcripts from both genes during embryogenesis showed that mapta can be spliced into isoforms with between four and six tubulin-binding repeats (4R - 6R), while maptb is mainly spliced into 3R isoforms. Expression of both genes is observed predominantly in the developing central nervous system. A particularly large isoform of maptb is specifically expressed in the trigeminal ganglion and in dorsal sensory neurons of the spinal cord. Changes in the subcellular ratio of 3R and 4R isoforms can have pathological consequences in mammals. The predominant production of 4R-6R isoforms from mapta and of 3R isoforms from maptb suggests that zebrafish embryos will be a useful tool with which to study the discrete functions and interactions of the 3R and 4R MAPT isoforms.

Pages 319-329
Paula J. Jansen, Dieter Lütjohann, Karin M. Thelen, Klaus von Bergmann, Fred van Leuven, Frans C.S. Ramaekers, Monique Mulder
Absence of ApoE Upregulates Murine Brain ApoD and ABCA1 Levels, But Does Not Affect Brain Sterol Levels, While Human ApoE3 and Human ApoE4 Upregulate Brain Cholesterol Precursor Levels
Abstract: Apolipoprotein E (apoE) is a regulator of peripheral cholesterol homeostasis, and the apoE-isoform E4 is a major risk factor for the development of Alzheimer’s disease (AD). Accumulating evidence suggests a key role for aberrant cholesterol metabolism in AD. We hypothesized that apoE-deficiency in mice not only affects cholesterol homeostasis in the periphery, but also in the brain, and that this can be restored by astrocyte-specific expression of human apoE3, but not apoE4. Using gas-chromatography mass-spectrometry, we found that absence of apoE in mice does not affect brain cholesterol homeostasis although serum sterol levels increase dramatically, especially when the apoE-knockout mice are fed a high fat diet. We provide evidence suggesting that apoD and the ATP-binding Cassette Transporter A1 (ABCA1) play a compensatory role in the apoE-deficient brain. Surprisingly, astrocyte-specific expression of human apoE3 or apoE4 in brains of apoE-knockout mice significantly increases brain levels of cholesterol and its precursors compared to control mice, indicative of an increased cholesterol synthesis rate in the brain. This increase is independent of the apoE-isoform, suggesting that the detrimental effect of apoE4 on the pathogenesis of AD is unlikely to be due to an apoE-isoform effect on brain cholesterol homeostasis.

Pages 331-337
Guido Straten, Gerhard W. Eschweiler, Walter Maetzler, Christoph Laske, Thomas Leyhe
Glial Cell-Line Derived Neurotrophic Factor (GDNF) Concentrations in Cerebrospinal Fluid and Serum of Patients with Early Alzheimer’s Disease and Normal Controls
Abstract: As neurotrophic factors play an important role in development and maintenance of global central nervous system (CNS) function, we supposed that glial cell-line derived neurotrophic factor (GDNF), which has been extensively studied for its survival promoting effects especially concerning catecholaminergic neurons, also plays a significant role in neurodegenerative disease characterized mainly by damage of cholinergic CNS neurons like AD. Here we compared GDNF concentrations in serum and cerebrospinal fluid (CSF) of patients with probable Alzheimer´s disease (AD) and normal controls (NC). While GDNF concentrations in CSF were significantly increased in patients with AD (291.7 ± 85.8 pg/ml) compared with NC subjects (218.7 ± 93.3 pg/ml, p = 0.012), GDNF concentration of AD patients (486.5 ± 72.3 pg/ml) in serum were significantly decreased compared with the NC group (711.5 ± 186.5 pg/ml, p < 0.001). Increased GDNF in CSF of AD might be due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease and/or impairment of CSF turnover. Decreased serum concentration of GDNF might be related to altered function of the blood brain barrier thus disturbing clearance or facilitating passover of potentially harmful metabolites.

Pages 339-344
Myeong Soo Lee, Eun-Jin Yang, Jong-In Kim, Edzard Ernst
Ginseng for Cognitive Function in Alzheimer’s Disease: A Systematic Review
Abstract: The objective of this review is to assess the clinical evidence for or against ginseng as a treatment for Alzheimer’s disease (AD). We searched 20 databases from their inception to January 2009 and included all randomized clinical trials (RCTs) of any type of Panax ginseng to treat human patients suffering from AD. Methodological quality was assessed using the Jadad score. Two RCTs met all inclusion criteria. They assessed the effectiveness of ginseng as an adjunct to drug therapy on cognitive function compared with conventional drug therapy. Their results suggested significant effect in favor of ginseng on the Mini-Mental Status Examination (n=174, weight mean difference (WMD), 1.85; 95% confidence intervals, CIs 0.88 to 2.82, P=0.0002) and on the Alzheimer’s Disease Assessment Scale (ADAS)-cognitive (n=174, WMD, 3.09; 95% CIs 1.08 to 5.09, P=0.003). Both of these studies are burdened with serious methodological limitations. In conclusion, the evidence for ginseng as a treatment of AD is scarce and inconclusive. Further rigorous trials seem warranted.

Pages 345-353
Pei-Ning Wang, Hsin-Chen Lee, Chun-Hui Wang, Yueh-Hsin Ping, Tsung-Yun Liu, Chin-Wen Chi, Ker-Nen Lin, Hsu-Chih Liu
Heteroplasmy of Mitochondrial D310 Mononucleotide Repeat Region in the Blood of Patients with Alzheimer’s Disease
Abstract: There is increasing evidence of oxidative stress in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Because mitochondrial DNA (mtDNA) is susceptible to oxidative damage, somatic mtDNA mutations may be induced by oxidative stress. Most of the studies examining mitochondrial mutations have been performed on postmortem brain tissues of AD patients. This study examined peripheral blood samples of AD and MCI patients to determine if peripheral mtDNA mutations are associated with these two conditions. A total of 236 subjects, including 71 AD patients, 84 amnestic MCI patients, 41 cognitively normal aging controls, and 40 young controls, were recruited. There was heteroplasmy of the mtDNA D310 polycytosine repeat region in 37 of 71 (52.1%) AD patients and this was significantly more frequent than in MCI patients (31.0%), normal aging (31.7%), and young controls (27.5%). However, subjects with amnestic MCI did not have a significantly higher rate of heteroplasmy in D310 than cognitively normal elderly subjects. The heteroplasmic alterations of D310 were more frequently in subjects with a larger number of polycytosine repetitions. Insertion of cytosine was the most common mutation type. The results suggest that mutations of mtDNA 310 region are frequently present in the peripheral blood of AD patients. Further prospective investigations to determine if MCI subjects with D310 mutations develop AD is warranted.

Pages 355-363
Meeting Report from the Alzheimer Research Forum
7th Annual Mild Cognitive Impairment (MCI) Symposium: Focus on Early Alzheimer’s Disease and Non-Alzheimer’s Prodromal Dementia, Miami, Florida, 27-28 March, 2009

Pages 365-366
Book Review: Ischemia and Loss of Vascular Autoregulation in Ocular and Cerebral Diseases: A New Perspective by Maurice E. Langham, Springer-Verlag New York, LLC, 2009, 192 pp. Reviewed by Joseph LaManna.

Mini-Forum on Roles of Amyloid-β and Tau Phosphorylation in Neuronal Repair and Protection (Guest Editor: Garth Bissette)

Pages 369-370
Garth Bissette
Preface: Mini-Forum: Roles of Amyloid-β and Tau Phosphorylation in Neuronal Repair and Protection

Pages 371-380
Mini-Forum Article
Garth Bissette
Does Alzheimer’s Disease Result from Attempts at Repair or Protection After Transient Abstract: This review explores the data indicating that the initial production of amyloid-β precursor protein and phosphorylated tau are associated with physiological mechanisms for repair or protection of neurons exposed to significant disturbances in homeostasis. Stimuli as diverse as head injury, inhaled anesthetic agents, stimulant drugs, and both physiological (restraint) and psychological stress (social isolation) have been shown to increase brain expression of amyloid-β and hyperphosphorylated tau without accompanying neurodegeneration. This review aims to encompass these responses as indicators of normal physiological processes that, in the case of Alzheimer’s disease, are either unable to successfully repair or protect vulnerable neuronal populations from eventual neurodegeneration, but that are necessary components of an integrated nervous system that would be more susceptible to pathology if such processes were blocked in an attempt to minimize or prevent future damage.

Pages 381-400
Mini-Forum Article
Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov
Amyloid-β, Tau Protein, and Oxidative Changes as a Physiological Compensatory Mechanism to Maintain CNS Plasticity under Alzheimer’s Disease and Other Neurodegenerative Conditions
Abstract: In this review, we propose that the neurodegenerative changes in the neurochemistry of amyloid-β (Aβ) aggregation, tau phosphorylation, cytoskeleton rearrangement, oxidative stress, and lipid peroxidation in Alzheimer’s disease (AD), and a number of other neurodegenerative diseases, are secondary pathological features. In fact, we believe that these phenomena represent natural compensatory mechanisms for impaired primary neurodegeneration, membrane dynamic deterioration, and/or associated failures of neurotransmission, synaptic function, and neuroplasticity. Physiologically, Aβ, lipid peroxidation, and tau protein may function to sense changes in activity-dependent membrane properties and therefore biochemically modulate membrane lipid homeostasis for more efficient synaptic action. As such, the previously proposed therapeutic tackling of amyloid, tau, oxidative stress, and other brain disease markers may have no ability to cure AD or other devastating central nervous system pathologies and peripheral nervous system diseases. This unfortunate realization provides a wake-up call to the neuroscience community, demanding open-minded approach.

Pages 401-412
Mini-Forum Article
Mikko Hiltunen, Thomas van Groen, Jukka Jolkkonen
Functional Roles of Amyloid-β Protein Precursor and Amyloid-β Peptides: Evidence from Experimental Studies
Abstract: Amyloid-β (Aβ) has remained a central feature in research into Alzheimer’s disease (AD). Yet the function of the amyloid-β protein precursor (AβPP) and its processing products in the central nervous system is controversial. This review examines experimental literature from cell cultures to transgenic AD and brain injury models with a special emphasis on the functional role of AβPP and AβPP-derived peptides. AβPP knock-out mice exhibit severe metabolic abnormalities and behavioral deficits, indicating an important physiological function of AβPP. Also, an increasing body of evidence suggests that while Aβ is undoubtedly linked to neurodegeneration, the soluble amino-terminal fragment of AβPP (sAβPPα) has neuroprotective, neurotrophic, and cell adhesive functions. Moderate overexpression of human AβPP in rodents does not produce apparent Aβ pathology and has no significant effect on cognitive or sensorimotor behavior and, surprisingly, may even provide histological neuroprotection against focal cerebral ischemia. In contrast, phenotypes with more severe Aβ pathology show impaired cognitive performance, increased vulnerability to brain ischemia and trauma, and less favorable functional outcome even before Aβ deposition. A delicate balance in AβPP processing seems to determine its functional consequences. Thus, it is tempting to speculate that promotion of α-secretase-mediated cleavage of AβPP, which leads to increased sAβPPα production, provides a novel therapeutic strategy in the treatment of AD and brain injury.

Pages 413-417
Mini-Forum Article
Kaj Blennow and Henrik Zetterberg
Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease
Abstract: Research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer’s disease (AD), which has been translated into an ongoing development of disease-modifying treatments. These new drug candidates are targeted on inhibiting amyloid-β (Aβ) production and aggregation or tau aggregation. If these drugs prove to be efficient, diagnostic tools enabling early diagnosis of AD will be of great value. Also in drug development, it is important to co-develop biomarkers to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). The core candidate CSF biomarkers Aβ42, total tau (T-tau), and phosphorylated tau (P-tau) have been shown to have a high diagnostic performance to identify AD also in the early phase of the disease. This paper reviews recent research advances on these CSF biomarkers for use in clinical diagnosis and in clinical trials in AD.

Pages 419-427
Mini-Forum Article
Parekkat M. Menon, Jean Paul Vonsattel, Paul R. Jolles
Brain Imaging and Neuropathologic Mechanisms in Alzheimer’s Disease: Vascular Versus Neurodegenerative and Amyloid-β Versus Tau
Abstract: Over the past several decades, there has been extensive research devoted toward determining the cause of Alzheimer’s disease. Numerous biochemical, histological, and imaging investigations have elegantly characterized the neuropathologic and functional changes associated with AD. Proponents of one theory or another can find supporting data among the myriad of studies in the literature. This paper attempts to summarize some of the major conclusions and controversies in imaging literature (especially, magnetic resonance imaging and nuclear medicine) in relation to pathogenesis theories of Alzheimer’s disease. In spite of considerable progress, the primary cause of Alzheimer’s disease remains elusive.

Pages 429-445
Mini-Forum Article
Inga Kadish, Thomas van Groen
Lesion-Induced Hippocampal Plasticity in Transgenic Alzheimer’s Disease Mouse Models: Influences of Age, Genotype, and Estrogen
Abstract: We have studied entorhinal cortex lesion-induced sprouting in the hippocampus in young, adult, and aged control and transgenic Alzheimer’s disease model mice. The entorhinal cortex was unilaterally, partially lesioned, and four weeks later the subsequent axonal sprouting in dentate gyrus was analyzed. Our data demonstrate that young and adult, control and amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) mice display a significantly increased density of staining for synaptophysin in dentate gyrus, indicative of axonal sprouting. However, whereas young and adult mice demonstrate sprouting, aged mice (control and AβPP/PS1) do not show a significant upregulation of synaptophysin staining following the lesions. In contrast, aged mice overexpressing PS1 show an increased regenerative response compared to age-matched control mice and mice overexpressing AβPP which do not show sprouting. Further, the data demonstrate that a significant Aβ load in the dentate gyrus does not prevent axonal sprouting. Lastly, only aged mice show significant shrinkage of the molecular layer of dentate gyrus following entorhinal cortex lesions. Further, adult ovariectomized females (control and AβPP/PS1) are significantly reduced in their plasticity following lesions. Taken together, the data indicate that amyloid-β deposits do not negatively impact plasticity in the brain and that overexpression of AβPP is not beneficial, but that normal estrogen levels are beneficial for plasticity.

Pages 447-452
Mini-Forum Article
Rudy J. Castellani, Hyoung-gon Lee, Sandra L. Siedlak, Akihiko Nunomura, Takaaki Hayashi, Masao Nakamura, Xiongwei Zhu, George Perry, Mark A. Smith (Handling Editor: Jesus Avila)
Reexamining Alzheimer’s Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid-β
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. Attention, not surprisingly, focused on amyloid-β as the major pathogenic mechanism, with the ultimate goal of selective amyloid-β targeting as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on “proteinopathies” and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.

Pages 453-457
Mini-Forum Article
Robert A. Rissman
Stress-Induced Tau Phosphorylation: Functional Neuroplasticity or Neuronal Vulnerability?
Abstract: Abnormally phosphorylated tau protein is a key component of the pathology seen in neurodegenerative tauopathies, such as Alzheimer’s disease (AD). Despite its association with disease, tau phosphorylation (tau-P) also plays an important role in neuroplasticity, such as dendritic/synaptic remodeling seen in the hippocampus in response to environmental challenges, such as stress. To define the boundaries between neuroplasticity and neuropathology, studies have attempted to characterize the paradigms, stimuli, and signaling intermediates involved in stress-induced tau-P. Supporting an involvement of stress in AD are data demonstrating alterations in stress pathways and peptides in the AD brain and epidemiological data implicating stress exposure as a risk factor for AD. In this review, the question of whether stress-induced tau-P can be used as a model for examining the relationship between functional neuroplasticity and neuronal vulnerability will be discussed.

Pages 459-469
Mini-Forum Article
Hongxin Dong and John G. Csernansky
Effects of Stress and Stress Hormones on Amyloid-β Protein and Plaque Deposition
Abstract: Growing evidence indicates that physical and psychosocial stressors, in part acting through the hypothalamic-pituitary-adrenal (HPA) axis, may accelerate the process of Alzheimer’s disease (AD). In this review, we summarize recent research related to the effects of stress and stress hormones on the various disease process elements associated with AD. Specifically, we focus on the relationships among chronic stressors, HPA axis activity, amyloid-β protein, and amyloid-β plaque deposition in mouse models of AD. The potential mechanisms by which stress and stress-related components, especially corticotrophin-releasing factor and its receptors, influence the pathogenesis of AD are discussed.

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