Journal of Alzheimer's Disease - Volume 19, issue 1

Authors: Matsuda, Noriyuki | Tanaka, Keiji

Article Type: Review Article

Abstract: About twenty years ago, an abnormal enrichment of ubiquitin in the inclusion bodies of various neurodegenerative disorders was reported. To date, this phenotype has been a diagnostic feature of many neurodegenerative disorders including Alzheimer's and Parkinson's diseases (PD). Because ubiquitin tags proteins that must be eliminated from cells, thereby targeting them for proteasomal degradation, many scientists believed that the ubiquitin-proteasome system (UPS) was inactivated in these neurodegenerative disorders. This inactivation would lead to an accumulation of ubiquitylated proteins with their concomitant aggregation into inclusion bodies and subsequent neuronal death. This hypothesis was further fuelled by the discovery that parkin, the …causal gene of autosomal recessive juvenile Parkinsonism, functions as a ubiquitin ligase. However, recent findings by several groups demonstrated that ubiquitylation is also relevant to the autophagy system, with parkin promoting autophagy of dysfunctional mitochondria following the loss of mitochondrial membrane potential. These novel topics do not necessarily mean that the proteasome is involved in neurodegeneration of PD. In this review, we describe current evidence and controversies regarding the relationship between UPS and neurodegenerative disorders such as PD, and discuss several scientific discrepancies that await further clarification. Show more

Keywords: Autophagy, K63, parkin, Parkinson's disease, proteasome, ubiquitin

DOI: 10.3233/JAD-2010-1231

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 1-9, 2010

Authors: Albani, Diego | Polito, Letizia | Forloni, Gianluigi

Article Type: Review Article

Abstract: Sirtuins are a family of conserved proteins with deacetylase and ADP-ribosyltransferase activity. In humans they are coded by seven genes (SIRT1-7). The most widely investigated and best known sirtuin is SIRT1, which can be activated by the natural phytocompound resveratrol and plays a role in several physiologic (embryogenesis, glucose metabolism, apoptosis, autophagy, chromatin integrity, and transcriptional state) and pathologic (diabetes, cancer, cardiovascular disorders, and neurodegeneration) conditions. In the field of neurodegeneration, resveratrol and SIRT1 have proved beneficial in in vitro and in vivo models of Alzheimer's disease (AD), reducing amyloid-β protein accumulation, considered one of the pathogenic mechanisms. In contrast …to these promising biological data, however, genetic studies linking SIRT1 variability to AD are negative (this is the case for other sirtuins too, e.g., SIRT3). In this review, we summarize the in vitro, in vivo, and genetic experimental results linking SIRT1 and the other sirtuins to AD, while a description of sirtuins' biochemical features and modulating compounds, as well as sirtuins' involvement in other neurodegenerative disorders are discussed as collateral aims. Show more

Keywords: Alzheimer's disease, genetics, neurodegeneration, resveratrol, review, SIRT1, Sirtuin

DOI: 10.3233/JAD-2010-1215

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 11-26, 2010

Authors: Brewer, Gregory J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-1238

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 27-30, 2010

Authors: Cui, Pei-Jing | Zheng, Lan | Cao, Li | Wang, Ying | Deng, Yu-Lei | Wang, Gang | Xu, Wei | Tang, Hui-Dong | Ma, Jian-Fang | Zhang, Ting | Ding, Jian-Qing | Cheng, Qi | Chen, Sheng-Di

Article Type: Short Communication

Abstract: We conducted a case-control study to determine the prevalence of the CALHM1 P86L polymorphism (rs2986017) in patients with Alzheimer's disease (AD) in the Chinese population of mainland China, and also to clarify whether this polymorphism is a risk factor for AD. Fourteen heterozygous P86L carriers were identified among 198 AD patients. One control subject was also found to be a P86L heterozygous carrier. The allelic frequencies of the AD patients and control subjects were found to be significantly different. Our study indicates that the CALHM1-P86L polymorphism is associated with AD in the ethnic Chinese Han.

Keywords: Alzheimer's disease, CALHM1, P86L, polymorphism

DOI: 10.3233/JAD-2010-1207

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 31-35, 2010

Authors: Huesa, Gema | Baltrons, María Antonia | Gómez-Ramos, Pilar | Morán, Asunción | García, Agustina | Hidalgo, Juan | Francés, Silvia | Santpere, Gabriel | Ferrer, Isidre | Galea, Elena

Article Type: Research Article

Abstract: RhoGTPases control cytoskeleton dynamics thereby modulating synaptic plasticity. Because Alzheimer's disease (AD) is characterized by synaptic dysfunction, we sought to determine whether the expression, activity, or localization of the GTPases RhoA, Rac1 and Cdc42, as well as p21-PAK, a downstream target of Rac1/Cdc42, were altered in 18-month-old AβPP Tg2576 mice (Swedish mutation) or in brains from patients with AD and, for comparison in the case of RhoA, Pick's disease (PiD), a neurodegenerative disorder characterized by hyper-phosphorylated tau accumulation. Immunohistochemical analyses revealed a distinct localization of each RhoGTPase in synapses, dendrite shafts, neuronal bodies, or astrocytes. The association of RhoA with …synapses and dendritic microtubules was confirmed by electron microscopy. In AβPP mice, RhoA expression decreased in synapses and increased in dystrophic neurites, suggesting altered subcellular targeting of RhoA. In AD, RhoA immunostaining decreased in the neuropil and markedly increased in neurons, co-localizing with hyperphosphorylated tau inclusions, as though RhoA were sequestered by neurofibrillary tangles. Additionally, total RhoA protein was lower in the AD brain hippocampus, reflecting loss of the membrane bound, presumably active, GTPase. RhoA colocalized with hyperphosphorylated tau in PiD, again suggesting that altered subcellular targeting of RhoA is related to neurodegeneration. No major immunohistochemical changes were observed for Rac1, Cdc42, or p21-PAK, thus identifying RhoA among RhoGTPases as a possible therapeutic target in AD. Show more

Keywords: Actin, cytoskeleton, microtubules, neurofibrillary tangles, Pick's disease, synaptic terminals, tau

DOI: 10.3233/JAD-2010-1203

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 37-56, 2010

Authors: Cupidi, Chiara | Capobianco, Raffaella | Goffredo, Donato | Marcon, Gabriella | Ghetti, Bernardino | Bugiani, Orso | Tagliavini, Fabrizio | Giaccone, Giorgio

Article Type: Research Article

Abstract: The relationship between amyloid-β (Aβ) deposition and tau-related neurofibrillary changes is a key issue in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to investigate the extent and cortical distribution of Aβ and tau pathology, their mutual links and their correlation with the duration of the disease in thirty-nine patients with fully expressed AD. By tau immunohistochemistry, we identified different patterns of distribution of neurofibrillary changes that were ascribed to Braak stage V and VI. The disease duration was longer in patients at Braak stage VI than in those at V. Morphometric analysis carried out in …several neocortical areas demonstrated that Aβ load was not uniform among individuals and also varied in the same patient throughout the neocortex, showing decreased severity from associative fields in the premotor and primary motor areas. Aβ load was higher at Braak stage VI than at stage V and correlated positively with disease duration in primary motor cortex and in superior temporal gyrus. Overall, we documented a marked heterogeneity in the extent of Aβ deposition even in AD brains at final stages of disease that cannot be completely explained by a simple, regular build up of this pathologic protein in the cerebral cortex during the course of the disease. This study may be relevant for the correct evaluation of therapeutic strategies for AD that specifically address Aβ pathology. Show more

Keywords: Alzheimer's disease, amyloid-β burden, Braak staging, immunohistochemistry, morphometry, neurofibrillary tangles, senile plaques, tau protein

DOI: 10.3233/JAD-2010-1205

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 57-68, 2010

Authors: Heinzen, Erin L. | Need, Anna C. | Hayden, Kathleen M. | Chiba-Falek, Ornit | Roses, Allen D. | Strittmatter, Warren J. | Burke, James R. | Hulette, Christine M. | Welsh-Bohmer, Kathleen A. | Goldstein, David B.

Article Type: Research Article

Abstract: Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the …first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation. Show more

Keywords: Alzheimer's disease, copy number variation, dementia, genome-wide association study

DOI: 10.3233/JAD-2010-1212

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 69-77, 2010

Authors: Bulloj, Ayelén | Leal, María C. | Xu, Huaxi | Castaño, Eduardo M. | Morelli, Laura

Article Type: Research Article

Abstract: The accumulation of amyloid-β (Aβ) peptides in senile plaques is one of the hallmarks of Alzheimer's disease (AD) progression. The endocytic pathway has been proposed as a major subcellular site for Aβ generation while the compartments in which Aβ-degrading proteases interact with Aβ are still elusive. It was suggested that extracellular Aβ degradation may take place by plasma-membrane associated proteases or by extracellular proteases, among which insulin-degrading enzyme (IDE) is the most relevant. However, the mechanisms of IDE secretion are poorly understood. In the present study we used N2a cells to explore if IDE is indeed released through exosomes and …the effect of exosomes release on extracellular levels of Aβ. We demonstrated that proteolytically-active plasma membrane associated-IDE is routed in living N2a cells to multivesicular bodies and subsequently, a major fraction is sorted to exosomes. We described that extracellular IDE levels decrease if the generation of multivesicular bodies is interfered and may be positively modulated by exosomes release under stress-induced conditions. Our results reinforce the relevance of functional IDE in the catabolism of extracellular Aβ. Show more

Keywords: Alzheimer's disease, amyloid-β, calcium, exosomes, hypoxia, insulin-degrading enzyme, multivesicular bodies, peptide degradation, Rab11-GTPase, VPS4

DOI: 10.3233/JAD-2010-1206

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 79-95, 2010

Authors: Fujimura, Robert K. | Reiner, Teresita | Ma, Fangchao | Phillips, Virginia | de las Pozas, Alicia | Dickson, Dennis W. | Roos, Bernard A. | Howard, Guy A. | Perez-Stable, Carlos

Article Type: Research Article

Abstract: The clinical hallmark of Alzheimer's disease (AD) is impairment of cognition associated with loss of synapses, accumulation of amyloid-β (Aβ) both within neurons and as extracellular deposits, and neurofibrillary degeneration composed of phospho-tau. Neurons in the hippocampus are among those that are most vulnerable. The purpose of this study was to investigate the expression of genes associated with cognition, synapse, and mitochondrial function in hippocampal neurons of AD compared to normal individuals. Neurons from the hippocampus with intraneuronal Aβ immunoreactivity were captured with laser microdissection; RNA was extracted; and levels of brain-derived neurotrophic factor (BDNF), TrkB (BDNF receptor), dynamin-1 (DYN), …and cytochrome C oxidase subunit II (COX2) were assessed with quantitative real-time polymerase chain reaction. We found no significant differences in the expression of these genes in AD between neurons associated with Aβ compared to those lacking Aβ immunoreactivity. Double immunofluorescence microscopy showed the number of hippocampal neurons coexpressing Aβ or phospho-tau and either BDNF, TrkB, or DYN was similar in AD and controls. Our results suggest that neither intraneuronal Aβ nor phospho-tau has obligatory effects on reducing the expression of genes important for memory and cognition in hippocampus of AD. Show more

Keywords: Amyloid-β, brain-derived neurotrophic factor (BDNF), cytochrome C oxidase subunit II (COX2), double immunofluorescence, dynamin-1 (DYN), qRT-PCR, phospho-tau

DOI: 10.3233/JAD-2010-1216

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 97-109, 2010

Authors: Borroni, Barbara | Alberici, Antonella | Grassi, Mario | Turla, Marinella | Zanetti, Orazio | Bianchetti, Angelo | Volta, Giorgio Dalla | Rozzini, Renzo | Gilberti, Nicola | Bellelli, Giuseppe | Padovani, Alessandro

Article Type: Research Article

Abstract: Frontotemporal Lobar Degeneration (FTLD) has always been considered a rare disorder, but only a few epidemiologic studies are available. The aim of the present work was to ascertain all FTLD patients in a Northern Italy area from January 2001 to December 2008, and to estimate the disease prevalence. On the census day, 213 FTD patients were still alive, resulting in an overall prevalence of 17.6 per 100,000 inhabitants. The prevalence of FTLD in patients aged 45–65 years was 22 per 100,000 inhabitants (95% CI=17–27). The prevalence of FTLD was the highest in patients aged 66–75 (78 per 100,000 inhabitants, 95% …CI=56–100), and it was still high over 75 years (54 per 100,000 inhabitants, 95% CI=36–69). FTLD is a more common form of dementia than previously recognized. Our results claimed that FTLD is not only an early-onset disorder, but it is frequent in advanced age as well. Show more

Keywords: Epidemiology, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, prevalence, rare disease

DOI: 10.3233/JAD-2010-1208

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 111-116, 2010