Journal of Alzheimer's Disease - Volume 16, issue 1

Authors: Wasling, Pontus | Daborg, Jonny | Riebe, Ilse | Andersson, My | Portelius, Erik | Blennow, Kaj | Hanse, Eric | Zetterberg, Henrik

Article Type: Review Article

Abstract: Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-β (Aβ) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Aβ is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Aβ, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review …the literature on the possible physiological roles of Aβ and its precursor protein AβPP during development with special focus on electrophysiological findings. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, development, long-term depression, long-term potentiation, synaptic plasticity

DOI: 10.3233/JAD-2009-0918

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 1-14, 2009

Authors: Huang, Han-Chang | Jiang, Zhao-Feng

Article Type: Review Article

Abstract: The neuropathology associated with Alzheimer's disease (AD) is characterized by the presence of extracellularly neuritic plaques, intracellularly neurofibrillary tangles and the loss of basal forebrain cholinergic neurons. The neuritic plaque is composed of a core of amyloid-β peptide (Aβ) while the neurofibrillary tangles contain phosphorylated tau protein, and, as such, both Aβ and tau are important molecules associated with AD. In healthy human bodies, clearance mechanisms for Aβ are available; yet if clearance fails, Aβ accumulates, increasing the risk of neurotoxicity in the brain. Tau, one of the main microtubule-associated proteins, will be hyperphosphorylated and lose the ability to bind …microtubules when the homeostasis of phosphorylation and dephosphorylation is disturbed in neurons. Accumulated Aβ and hyperphosphorylated tau are thought to be coexistent. Research on the pathological changes in AD indicates that accumulated Aβ in vivo may initiate the hyperphosphorylation of tau. Also, the signal transduction pathways of tau hyperphosphorylation may be related to accumulated Aβ. In this review, we will discuss how Aβ accumulates, how tau protein is hyperphosphorylated, and how accumulated Aβ initiates hyperphosphorylation of tau protein in AD. Show more

Keywords: α7nAChR, amyloid-β peptide (Aβ), oxidative stress, PI3K/Akt, tau protein

DOI: 10.3233/JAD-2009-0960

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 15-27, 2009

Authors: Nelson, Peter T. | Kryscio, Richard J. | Abner, Erin L. | Schmitt, Frederick A. | Jicha, Gregory A. | Mendiondo, Marta S. | Cooper, Greg | Smith, Charles B. | Markesbery, William R.

Article Type: Short Communication

Abstract: Dementia can be caused by different diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or both (AD + DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD + DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n = 156 ). Patients with important concomitant pathology (n = 5 ) or patients that were profoundly demented at recruitment (intake MMSE < 20 ; n = 86 ) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients …with pathologically-diagnosed AD + DLB (n = 25 ) lost cognitive capacity faster than patients with AD alone (n = 40 ). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline. Show more

Keywords: Acetycholinesterase, acetylcholinesterase inhibitors, Alzheimer's disease, cholinesterase, dementia with Lewy bodies, neuropathology

DOI: 10.3233/JAD-2009-0926

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 29-34, 2009

Authors: Ignatov, Ignat | Belden, Christine | Jacobson, Sandra | Connor, Donald | Sabbagh, Marwan N.

Article Type: Short Communication

Abstract: The objective of this study was to describe a case of Alzheimer's disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer's disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer's disease with decline on the Mini-Mental Status Examination from a score of 25 …to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer's disease is rare in Apo E2 homozygotes but can occur. Show more

Keywords: Alzheimer's disease, apolipoprotein E2, homozygote, PET scan

DOI: 10.3233/JAD-2009-0932

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 35-38, 2009

Authors: Zhang, Jia-yu | Peng, Caixia | Shi, Hairong | Wang, Shaohui | Wang, Qun | Wang, Jian-zhi

Article Type: Research Article

Abstract: The autophagic lysosomal system contributes to the removal of cytosolic components, and abnormality of lysosomal proteases has been reported in the brain of patients with Alzheimer's disease (AD). However, the role of lysosome in tau degradation is still elusive. Here, we infused chloroquine, 3-methyladenine or rapamycin into rat hippocampus or the lateral ventricle to manipulate the autophagic activity and measured the levels of tau protein by Western blotting. We unexpectedly observed that the level of different tau species decreased upon inhibition of lysosomal proteases or macroautophagy by chloroquine or 3-methyladenine. Furthermore, induction of autophagic activity by rapamycin did not induce …degradation of tau proteins. To explore the underlying mechanisms for the increased tau degradation induced by autophagic inhibition, we used MG-132, an inhibitor of proteasome and calpain. We found that simultaneous inhibition of proteasome and calpain by MG-132 prevented the chloroquine-induced tau degradation. Further studies demonstrated that the activity of calpain was elevated whereas the activity of proteasome was suppressed in response to inhibition of autophagy by 3-methyladenine or chloroquine. Our data suggest that the lysosomal autophagic system may not degrade tau in the normal adult rat brain and inhibition of autophagy may induce tau proteolysis through activating calpain. Show more

Keywords: Autophagy, calpain, degradation, tau

DOI: 10.3233/JAD-2009-0908

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 39-47, 2009

Authors: Zhao, Wei | Wang, Jun | Ho, Lap | Ono, Kenjiro | Teplow, David B. | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Recent studies suggest that certain cardiovascular antihypertensive agents decrease the incidence of Alzheimer's disease. Based on this evidence and the fact that Aβ aggregation into high-molecular-weight-soluble oligomeric Aβ species is known to directly induce cognitive impairment, we tested the possibility that certain antihypertensive compounds may affect the progression of Alzheimer's disease, at least in part by influencing the formation of Aβ oligomers. High throughput screening of 55 commercially available antihypertensive drugs identified four compounds that significantly reduced Aβ1–42 oligomerization in a dose dependent manner. These four compounds, furosemide (diuretic), nitrendipine (calcium channel blocker), candesartan cilextil (angiotensin II receptor antagonist) …and diazoxide (vasodilator) showed no detectable Aβ lowering activities in primary neuron cultures generated from Tg2576 mouse embryos. However, furosemide, nitrendipine and candesartan cilextil prevented oligomerization of both Aβ1–40 and Aβ1–42 in vitro. Furosemide also dissociated pre-aggregated Aβ1–42 oligomers. Furthermore, short term furosemide treatment resulted in decreased amount of Aβ oligomers in the brain of Tg2576 mice. Our studies suggest that certain antihypertensive compounds may prevent AD-type neuropathology through inhibition of Aβ oligomer formation. Show more

Keywords: Alzheimer's disease, amyloid-β, hypertension, oligomerization

DOI: 10.3233/JAD-2009-0925

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 49-57, 2009

Authors: Ho, Lap | Chen, Ling Hong | Wang, Jun | Zhao, Wei | Talcott, Stephen T. | Ono, Kenjiro | Teplow, David | Humala, Nelson | Cheng, Alice | Percival, Susan S. | Ferruzzi, Mario | Janle, Elsa | Dickstein, Dara L. | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and …Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms. Results from these studies suggest the possibility of developing a “combination” of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Aβ-related mechanisms. Show more

Keywords: Alzheimer's disease dementia, amyloid-β protein precursor (AβPP), high-molecular-weight amyloid-β oligomer species, polyphenols

DOI: 10.3233/JAD-2009-0916

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 59-72, 2009

Authors: Ray, Monika | Zhang, Weixiong

Article Type: Research Article

Abstract: The assessment of the relationship between gene expression profiling, clinical and histopathological phenotypes would be better suited to understanding Alzheimer's disease (AD) pathogenesis. We developed a multiple linear regression (MLR) method to simultaneously model three variables – Mini-Mental Status Examination (MMSE) score, neurofibrillary tangles (NFT) score and gene expression profile – to identify significant genes. These genes were also used to distinguish subjects with incipient AD from healthy controls. Finally we investigated the behavior of the significant genes across the entorhinal cortex and hippocampus of AD subjects in two different Braak stages. Results indicate that integrating multiple phenotypic and gene …expression information of samples increases the power of methods while analyzing small datasets. The MLR method could identify significant genes at reasonable false discovery rates (FDRs), thereby providing a choice of reasonable FDRs. The accuracy in discriminating between subjects affected and unaffected by AD using MLR identified genes was high. We found that transcription and tumor suppressor responses do begin quite early in AD and therefore should be the target of drugs. Several genes were consistently up/down-regulated across the two brain regions and Braak stages and, therefore, can be used as predictive markers to detect AD at an earlier stage. Show more

Keywords: Alzheimer's disease, classification, gene selection, microarray data, Mini-Mental Status Examination, neurofibrillary tangles score

DOI: 10.3233/JAD-2009-0917

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 73-84, 2009

Authors: Eskelinen, Marjo H. | Ngandu, Tiia | Tuomilehto, Jaakko | Soininen, Hilkka | Kivipelto, Miia

Article Type: Research Article

Abstract: Caffeine stimulates central nervous system on a short term. However, the long-term impact of caffeine on cognition remains unclear. We aimed to study the association between coffee and/or tea consumption at midlife and dementia/Alzheimer's disease (AD) risk in late-life. Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were randomly selected from the survivors of a population-based cohorts previously surveyed within the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 or 1987 (midlife visit). After an average follow-up of 21 years, 1409 individuals (71%) aged 65 to 79 completed the re-examination in 1998. A total …of 61 cases were identified as demented (48 with AD). Coffee drinkers at midlife had lower risk of dementia and AD later in life compared with those drinking no or only little coffee adjusted for demographic, lifestyle and vascular factors, apolipoprotein E ε4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3–5 cups per day. Tea drinking was relatively uncommon and was not associated with dementia/AD. Coffee drinking at midlife is associated with a decreased risk of dementia/AD later in life. This finding might open possibilities for prevention of dementia/AD. Show more

Keywords: Alzheimer's disease, coffee, dementia, epidemiology, tea

DOI: 10.3233/JAD-2009-0920

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 85-91, 2009

Authors: Bowman, Gene L. | Dodge, Hiroko | Frei, Balz | Calabrese, Carlo | Oken, Barry S. | Kaye, Jeffrey A. | Quinn, Joseph F.

Article Type: Research Article

Abstract: The brain maintains high levels of ascorbic acid (AA) despite a concentration gradient favoring diffusion from brain to peripheral tissues. Dietary antioxidants, including AA, appear to modify the risk of Alzheimer's disease (AD). The objective of this study was to test the hypothesis that neurodegeneration in AD is modified by brain levels of AA. Thirty-two patients with mild to moderate AD participated in a biomarker study involving standardized clinical assessments over one year. Cerebrospinal fluid (CSF) and serum were collected at baseline for AA and albumin content. Cognitive measures were collected at baseline and one year. CSF and plasma AA …failed to predict cognitive decline independently, however, CSF: plasma AA ratio did. After adding CSF Albumin Index (an established marker of blood-brain barrier integrity) to the regression models the effect of CSF: plasma AA ratio as a predictor of cognitive decline was weakened. CSF: plasma AA ratio predicts rate of decline in AD. This relationship may indicate that the CSF: plasma AA ratio is an index of AA availability to the brain or may be an artifact of a relationship between blood-brain barrier impairment and neurodegeneration. Show more

Keywords: Albumin, Alzheimer's disease, antioxidants, ascorbic acid, blood-brain barrier, cerebrospinal fluid, cognitive decline, vitamin C

DOI: 10.3233/JAD-2009-0923

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 93-98, 2009