Journal of Alzheimer's Disease - Volume 19, issue 3

Authors: Nicolia, Vincenzina | Fuso, Andrea | Cavallaro, Rosaria A. | Di Luzio, Andrea | Scarpa, Sigfrido

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3β (GSK3β) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3β causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A …C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls ABα C heterotrimers formation. Here we demonstrate that GSK3β and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3β protein increase and a modulation in phosphorylation sites that regulate GSK3β activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3β and PP2A, leading to abnormal hyperphosphorylated tau. Show more

Keywords: B vitamin, homocysteine, GSK3β, PP2A, S-adenosylmethionine

DOI: 10.3233/JAD-2010-1284

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 895-907, 2010

Authors: Di Maria, Emilio | Cammarata, Sergio | Parodi, Maria Isola | Borghi, Roberta | Benussi, Luisa | Galli, Marialaura | Galimberti, Daniela | Ghidoni, Roberta | Gonella, Davide | Novello, Cristina | Pollero, Valeria | Perroni, Lucia | Odetti, Patrizio | Scarpini, Elio | Binetti, Giuliano | Tabaton, Massimo

Article Type: Research Article

Abstract: Mild cognitive impairment is often considered a transitional condition prodromal to Alzheimer's disease. The dissection of genetic risk factors predisposing to mild cognitive impairment is paramount to assess the individual predisposition and reliably evaluate the effectiveness of early therapeutic interventions. We designed a cross-sectional analysis to test whether the occurrence of mild cognitive impairment is influenced by variations of the tau protein gene. The genotypes of seven polymorphisms tagging the major tau haplotypes were assayed on 186 patients with amnestic mild cognitive impairment and 191 unrelated controls. Association study was conducted by logistic regression including APOE genotype and age as …covariates. Case-control analysis showed that the common H1 haplotype is significantly overrepresented in patients (OR, 95% CI: 2.31, 1.52–3.51; p<0.001), whereas did not provide positive signals for any of the H1 sub-haplotypes that had been described as associated with Alzheimer's disease. This finding was confirmed when the ε4 allele of the APOE gene was taken into account (OR, 95% CI: 2.319, 1.492–3.603; p<0.001). These results firstly suggest that the risk of mild cognitive impairment is influenced by tau protein gene variations and that mild cognitive impairment shares a common genetic background with Alzheimer's disease. They may help elucidating the genetic risk to cognitive decline and designing effective clinical trials. Show more

Keywords: Alzheimer's disease, APOP, association study, MAPT, mild cognitive impairment, tau protein

DOI: 10.3233/JAD-2010-1285

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 909-914, 2010

Authors: Chakravarthy, Balu | Gaudet, Chantal | Ménard, Michel | Atkinson, Trevor | Brown, Leslie | LaFerla, Frank M. | Armato, Ubaldo | Whitfield, James

Article Type: Research Article

Abstract: The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-β (Aβ)1-42 oligomers that is accompanied by the downregulation of the Trk A neurotrophin receptor and by either upregulation or at least maintenance of the p75 neurotrophin receptor (p75NTR ), which can be stimulated by the accumulating Aβ1-42 peptides. Here we show that Aβ1-42 and its active fragment Aβ25-35 , but not Aβ42-1 , can at least double the level of p75NTR receptors in the membranes of model SH-SY5Y human neuroblastoma cells. We also show that p75NTR is upregulated in …the hippocampi of two strains of AD transgenic mice. Specifically, the level of the p75NTR receptor in the hippocampal membranes from 12–15 monthold AD-triple transgenic mice (3xTg-AD) harboring PS1M146V , AβPPSwe , and tauP301L was nearly twice that in hippocampal membranes from age-matched wild-type mice. Similarly, the level of p75NTR receptor in 7 month-old B6.Cg-Tg AD mice harboring PSEN1dE9 and AβPPSwe was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Aβ1-42 levels in the AD mice. Thus, it appears that it could be the accumulating Aβ1-42 that increases or at least prevents the downregulation of p75NTR receptors in key parts of AD brains. It is possible that when the Aβ1-42 accumulation reaches a critical level in the brain on the way to late-onset AD, the Aβ1-42 -induced p75NTR receptor signaling starts a vicious cycle that accelerates AD development because of the activated receptors' recently shown ability to stimulate Aβ1-42 production. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, human neuroblastomas, p75NTR (neurotrophin receptor), SH-SY5Y human neuroblastomas, transgenic mice

DOI: 10.3233/JAD-2010-1288

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 915-925, 2010

Authors: Yuan, Xiuli | Shan, Baoci | Ma, Yunchuan | Tian, Jiahe | Jiang, Kaida | Cao, Qiuyun | Wang, Ruimin

Article Type: Research Article

Abstract: Using statistical parametric mapping (SPM), we evaluate the feasibility and accuracy of 18 F -2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) for clinical diagnosis with characteristic hypo-metabolic regions, and examine the consistency of cerebral hypo-metabolism in Alzheimer's disease (AD) cross multicenters at both the group and the individual levels. Four groups of scan data including 39 AD patients and 52 healthy control subjects derived from three centers were analyzed and comparisons between patient subgroups or individual patient and relevant control population were performed using Two Sample T-test. In the group analysis, the hypo-metabolic regions of AD patients obtained from different PET …centers were similar and consistent. The common hypo-metabolic cerebral areas were located bilaterally in the posterior cingulate and medial parietal cortex, temporo-parietal cortex, prefrontal cortex, and the middle and inferior temporal gyrus (uncorrected, p<0.001). In the analysis of each individual subject, the location of declined posterior cingulate and medial parietal cortex, temporo-parietal cortex and temporal lobe were found highly consistent with relevant characteristic regions obtained in the group analysis and were selected for diagnosic purposes. Complete typical hypo-metabolic pattern was observed in 67% and 54% of AD patients in two sets of 3D scans, respectively. Only 27% and 33.3% patients showed full typical pattern in two sets of 2D scans. The results indicated that FDG PET measures and SPM can 4 provide a valuable reference for clinical diagnosis of AD patients. The potential influence of acquisition mode on the clinical diagnosis of AD was suggested for further evaluation. Show more

Keywords: Alzheimer's disease, hypo-metabolism, individual analysis, multicenter study, positron emission tomography

DOI: 10.3233/JAD-2010-1287

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 927-935, 2010

Authors: Maetzler, Walter | Schmid, Benjamin | Synofzik, Matthis | Schulte, Claudia | Riester, Karin | Huber, Heiko | Brockmann, Kathrin | Gasser, Thomas | Berg, Daniela | Melms, Arthur

Article Type: Research Article

Abstract: A large proportion of demented Lewy body disease patients have Alzheimer's disease (AD)- like pathology, in particular amyloid-β (Aβ) plaques. Cystatin C (CysC) is a carrier of soluble Aβ42 in the cerebrospinal fluid (CSF) and reduces Aβ plaque formation. The CST3 BB genotype leads to a reduced secretion of the protein in vitro and increases the risk for AD, suggesting that variability in the CST3 gene and CysC protein concentration may be associated with dementia in Lewy body disease. We therefore determined the CST3 genotype in 51 demented and 71 nondemented Lewy body disease patients, and in 52 controls, …as well as CSF CysC and Aβ42 levels from 132 of these subjects. The CST3 BB genotype was associated with lowered CSF CysC levels and with dementia. Demented Lewy body disease patients had decreased CSF CysC levels. The correlation between CSF CysC and Aβ42 levels was high in non-demented subjects, but poor in demented patients. We conclude that, in Lewy body disease, the CST3 BB genotype and low CSF CysC levels are associated with dementia, possibly through a disturbed elimination of soluble Aβ42 . Show more

Keywords: Amyloid, amyloidosis, CST3 gene, dementia with Lewy bodies, Parkinson's disease

DOI: 10.3233/JAD-2010-1289

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 937-942, 2010

Authors: Hyde, Zoë | Flicker, Leon | Almeida, Osvaldo P. | McCaul, Kieran A. | Jamrozik, Konrad | Hankey, Graeme J. | Chubb, S.A. Paul | Yeap, Bu B.

Article Type: Research Article

Abstract: Elevated levels of gonadotropins have been observed in patients with Alzheimer's disease and have been associated with poorer cognition in women, but not men. The aim of this study was to explore the relationship between gonadotropins and cognition in a cohort of 585 healthy, community-dwelling men aged 70–87 years. Cognitive function was assessed with the California Verbal Learning Test Second Edition (CVLT-II) and the Standardized Mini-Mental State Examination (SMMSE). Testosterone, sex hormone binding globulin, and luteinizing hormone levels were assayed from early morning sera. Free testosterone was calculated using mass action equations. In linear regression analyses, neither total nor free …testosterone levels were associated with measures of immediate or delayed recall. Higher levels of luteinizing hormone were associated with poorer performance on a measure of immediate recall (CVLT-II trials 1–5 total score) independent of total and free testosterone levels. The association remained after adjustment for age, educational attainment, and depression. In contrast, only total and free testosterone levels were associated with SMMSE score. These findings suggest a role for both androgens and gonadotropins in differing cognitive domains, and that gonadotropins may influence cognition independent of sex steroids. Show more

Keywords: Cognition, gonadotropins, luteinizing hormone, male aging, memory, testosterone

DOI: 10.3233/JAD-2010-1342

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 943-951, 2010

Authors: Liu, Xin-An | Liao, Kai | Liu, Rong | Wang, Hai-Hong | Zhang, Yao | Zhang, Qi | Wang, Qun | Li, Hong-Lian | Tian, Qing | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Phosphorylation of tau, a major microtubule-associated protein, has been recently discovered to affect cell apoptosis. While the phosphorylation of tau is dynamically regulated, the role of tau dephosphorylation in cell viability is elusive. Here, we observed that the cells bearing high level of the dephosphorylated tau at Tau-1 epitope were more vulnerable to the apoptosis induced by staurosporine, camptothecin, and hydrogen peroxide, though the general outcome of tau expression was still anti-apoptotic. Further studies demonstrate that co-expression of tau and protein phosphatase 2A catalytic subunit (PP2Ac), the most active tau phosphatase, potentiates cell apoptosis with a correlatively increased dephosphorylation of …tau and phosphorylation of Bcl-2 at Ser87 (pS87-Bcl2, the inactive form of the anti-apoptotic factor), whereas expression of PP2Ac alone in the absence of tau decreases the levels of pS87-Bcl2 and cleaved PARP, markers of early apoptosis. Finally, both tau and Bcl-2 were co-immunoprecipitated with PP2Ac, but the binding level of Bcl-2 with PP2Ac decreased prominently when tau was co-expressed. These data suggest that tau dephosphorylation by PP2Ac facilitates cell apoptosis with the mechanisms involving a failed dephosphorylation/activation of Bcl-2. Show more

Keywords: Apoptosis, Bcl-2, protein phosphatase, tau phosphorylation

DOI: 10.3233/JAD-2010-1294

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 953-962, 2010

Authors: Canu, Elisa | McLaren, Donald G. | Fitzgerald, Michele E. | Bendlin, Barbara B. | Zoccatelli, Giada | Alessandrini, Franco | Pizzini, Francesca B. | Ricciardi, Giuseppe K. | Beltramello, Alberto | Johnson, Sterling C. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Although it is established that Alzheimer's disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss …were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging. Show more

Keywords: Alzheimer's disease, diffusion weighted imaging, fractional anisotropy, mean diffusivity, microstructure

DOI: 10.3233/JAD-2010-1295

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 963-976, 2010

Authors: Shi, Yan-Qing | Huang, Tian-Wen | Chen, Li-Min | Pan, Xiao-Dong | Zhang, Jing | Zhu, Yuan-Gui | Chen, Xiao-Chun

Article Type: Research Article

Abstract: It is well established that the presence of soluble amyloid-β protein (Aβ) correlates with the severity of dementia in Alzheimer's disease (AD). Several lines of evidence indicate that cyclic AMP responsive element binding protein (CREB) and protein kinase A (PKA) are involved in soluble Aβ-trigged disruption of synaptic plasticity in early AD. Previously we demonstrated the beneficial effects of ginsenoside Rg1 on Aβ-induced neuronal insult. Therefore, in the present study, we examined the effects of long-term consumption of Rg1 on the cerebral Aβ content and PKA/CREB signaling molecules, as well as cognitive performance in senescence-accelerated mouse prone 8 (SAMP8). Notably, …a significant dose-dependent reduction of soluble Aβ1-40 was shown in the hippocampus of SAMP8 mice after administration with ginsenoside Rg1 for 3 months. Furthermore, Rg1 treatment resulted in a significant decrease of hippocampal PKA RIIα level (isoform IIα of the regulatory subunit of PKA). In contrast, phospho-CREB and brain derived neurotrophic factor (BDNF) levels were dramatically increased in the hippocampus of SAMP8 treated with Rg1. Additionally, administration of ginsenoside Rg1 consequently improved learning and memory outcomes in SAMP8 mice. These data suggest that long-term consumption of ginsenoside Rg1 may delay cognitive decline, associated with significant effects on Aβ generation, PKA/CREB activity, as well as BDNF content in the brain. These data provide further support for the therapeutic or intervention potency of ginsenoside Rg1 in the early stage of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, CREB, ginsenoside Rg1, PKA, senescence-accelerated mouse prone8

DOI: 10.3233/JAD-2010-1296

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 977-989, 2010

Authors: Granic, Ivica | Masman, Marcelo F. | (Kees) Mulder, Cornelis | Nijholt, Ingrid M. | Naude, Pieter J.W. | de Haan, Ammerins | Borbély, Emöke | Penke, Botond | Luiten, Paul G.M. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Misfolding, oligomerization, and aggregation of the amyloid-β (Aβ) peptide is widely recognized as a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have identified soluble Aβ oligomers as the main pathogenic agents and provided evidence that such oligomeric Aβ aggregates are neurotoxic, disrupt synaptic plasticity, and inhibit long-term potentiation. A promising therapeutic strategy in the battle against AD is the application of short synthetic peptides which are designed to bind to specific Aβ-regions thereby neutralizing or interfering with the devastating properties of oligomeric Aβ species. In the present study, we investigated the neuroprotective properties of the amyloid …sequence derived pentapeptide LPYFDa in vitro as well as its memory preserving capacity against Aβ42 -induced learning deficits in vivo. In vitro we showed that neurons in culture treated with LPYFDa are protected against Aβ42 -induced cell death. Moreover, in vivo LPYFDa prevented memory impairment tested in a contextual fear conditioning paradigm in mice after bilateral intrahippocampal Aβ42 injections. We thus showed for the first time that an anti-amyloid peptide like LPYFDa can preserve memory by reverting Aβ42 oligomer-induced learning deficits. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, β-sheet breaker peptides, behavioral tests, circular dichroism spectrometry, fear conditioning, hippocampus, molecular modeling, neuroprotection, primary cortical neurons

DOI: 10.3233/JAD-2010-1297

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 991-1005, 2010