Journal of Alzheimer's Disease - Volume 22, issue 2

Authors: Ji, Lina | Chauhan, Ved | Mehta, Pankaj | Wegiel, Jerzy | Mehta, Sangita | Chauhan, Abha

Article Type: Research Article

Abstract: Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43–63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young …DS (age 0.5–23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ40 and Aβ42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ40 (r2 = 0.7820, p < 0.01) and Aβ42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin. Show more

Keywords: Alzheimer's disease, amyloid-β protein, apoptosis, carboxyl-terminal fragment of gelsolin, Down syndrome

DOI: 10.3233/JAD-2010-101029

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 609-617, 2010

Authors: Subramanian, Sandhya | Ayala, Patricia | Wadsworth, Teri L. | Harris, Christopher J. | Vandenbark, Arthur A. | Quinn, Joseph F. | Offner, Halina

Article Type: Research Article

Abstract: The inflammatory status of the brain in patients as well as animal models of Alzheimer's disease (AD) has been extensively studied. Accumulation of activated microglia producing tumor necrosis factor-α and monocyte chemotactic protein-1 contribute to the pathology of the disease. However, little is known about the changes in the spleen and associated peripheral immunity that might contribute to AD pathology. The goal of this study was to characterize phenotypic and functional changes in spleen, blood and brain cell populations that contribute to development of an AD-like disease in a triple transgenic (3xTg-AD) mouse model. The 3xTg-AD mice had increased percentages …of brain Gr-1+ granulocytes, dendritic cells and macrophages, spleen and blood derived CD8+Ly6C+ memory T cells and CCR6+ B cells, as well as increased levels of secreted interleukin-6. Brain tissue from older 12 month old symptomatic 3xTg-AD female mice exhibited highly elevated mRNA expression of CCR6 compared to wild-type mice. Importantly, this pronounced increase in expression of CCR6 was also detected in brain and spleen tissue from pre-symptomatic 5–6 month old 3xTg-AD females and males. Our data demonstrate increased expression of CCR6 in the brain and peripheral immune organs of both pre-symptomatic and symptomatic 3xTg-AD mice, strongly suggesting an ongoing inflammatory process that precedes onset of clinical AD-like disease. Show more

Keywords: 3xTg-AD Mice, Alzheimer's Disease, CCR6, inflammation

DOI: 10.3233/JAD-2010-100852

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 619-629, 2010

Authors: Ginsberg, Stephen D. | Mufson, Elliott J. | Counts, Scott E. | Wuu, Joanne | Alldred, Melissa J. | Nixon, Ralph A. | Che, Shaoli

Article Type: Research Article

Abstract: Endocytic alterations are one of the earliest changes to occur in Alzheimer's disease (AD), and are hypothesized to be involved in the selective vulnerability of specific neuronal populations during the progression of AD. Previous microarray and real-time quantitative PCR experiments revealed an upregulation of the early endosomal effector rab5 and the late endosome constituent rab7 in the hippocampus of people with mild cognitive impairment (MCI) and AD. To assess whether these select rab GTPase gene expression changes are reflected in protein levels within selectively vulnerable brain regions (basal forebrain, frontal cortex, and hippocampus) and relatively spared areas (cerebellum and striatum), …we performed immunoblot analysis using antibodies directed against rab5 and rab7 on postmortem human brain tissue harvested from cases with a premortem clinical diagnosis of no cognitive impairment (NCI), MCI, and AD. Results indicate selective upregulation of both rab5 and rab7 levels within basal forebrain, frontal cortex, and hippocampus in MCI and AD, which also correlated with Braak staging. In contrast, no differences in protein levels were found in the less vulnerable cerebellum and striatum. These regional immunoblot assays are consistent with single cell gene expression data, and provide protein-based evidence for endosomal markers contributing to the vulnerability of cell types within selective brain regions during the progression of AD. Show more

Keywords: Basal forebrain, cerebellum, endosome, frontal cortex, hippocampus, mild cognitive impairment, rab GTPase, selective vulnerability, striatum

DOI: 10.3233/JAD-2010-101080

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 631-639, 2010

Authors: Ill-Raga, Gerard | Ramos-Fernández, Eva | Guix, Francesc X. | Tajes, Marta | Bosch-Morató, Mónica | Palomer, Ernest | Godoy, Juan | Belmar, Sebastián | Cerpa, Waldo | Simpkins, James W. | Inestrosa and, Nibaldo C. | Muñoz, Francisco J.

Article Type: Research Article

Abstract: Different mechanisms including oxidative stress are proposed for amyloid-β peptide (Aβ) neurotoxicity, and here we contribute to demonstrate that nitro-oxidative stress is playing a key role. Yeasts are a well-known model for H2 O2 toxicity. Interestingly, yeast cell wall prevents interaction of Aβ fibrils with membrane receptors or calcium channels and we found a significant viability reduction in yeasts when challenged with Aβ fibrils. Furthermore, iron and copper chelators, as well as the antioxidants glutathione and trolox, were neuroprotective on neuroblastoma cells and mouse hippocampal neurons challenged with Aβ fibrils. Glutathione prevents the oxidation, glycation and nitrotyrosination of cell …proteins induced by Aβ. Trolox protected neurons in cell viability studies, maintaining the vesicular transport integrity and preventing the trigger of apoptotic mechanisms. Interestingly, we have also found that brain derived neuronal factor (BDNF) and neurotrophin-3 (NT-3) were able to protect mouse hippocampal and cortical neurons against H2 O2 and Aβ fibrils. Considering that superoxide anion, produced by Aβ cell damage, and nitric oxide, whose production is altered in AD, react to form the highly reactive peroxynitrite anion, we studied the role of trolox to ameliorate the peroxynitrite cell damage. Finally, one of the major proteins to be nitrotyrosinated in AD, the triose phosphate isomerase (TPI) was assayed searching for a denitrase activity that could reverse intracellular nitrotyrosination. We have found that human neuroblastoma SH-SY5Y cells express a constitutive denitrase activity that partially denitrated nitro-TPI. Altogether, our results support a key role of nitro-oxidative stress in the neuronal damage induced by Aβ fibrils. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, antioxidants, oxidative stress, peroxynitrite, triose phosphate isomerase

DOI: 10.3233/JAD-2010-100474

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 641-652, 2010

Authors: Wang, Jun | Santa-Maria, Ismael | Ho, Lap | Ksiezak-Reding, Hanna | Ono, Kenjiro | Teplow, David B. | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly …attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain. Show more

Keywords: Aggregation, Alzheimer's disease, hyperphosphorylation, neurofibrillary tangles, tauopathies

DOI: 10.3233/JAD-2010-101074

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 653-661, 2010

Authors: Zhu, Yi-Cheng | Dufouil, Carole | Soumaré, Aïcha | Mazoyer, Bernard | Chabriat, Hugues | Tzourio, Christophe

Article Type: Research Article

Abstract: The clinical significance of dilated Virchow-Robin spaces (dVRS) remains unclear and their impact on cognitive performances has only been reported in small sample studies. Our aim was to assess the association between severity of dVRS and risk of incident dementia and cognitive decline in an elderly cohort. The degree of dVRS in both white matter and basal ganglia were ranked using high-resolution 3D MRI in a population-based sample of 1,778 non-demented participants from 65 to 80 years of age, who had a cerebral MRI at baseline. Cognitive function was assessed and dementia was diagnosed during a 4-year follow-up period. Cox …proportional hazard models were used to examine the association between dVRS degree on a four-level severity score and incident dementia. The relationship between dVRS degree and change in cognition was examined using linear mixed effect models. During 6,135 person-years of follow-up, 27 individuals developed dementia. The highest degree of dVRS was associated with a strong increase in the risk of incident dementia independently of other standard risk factors of dementia, both for dVRS in white matter (HR = 9.8, 95% CI 1.7–55.3) and in basal ganglia (HR = 5.8, 95% CI 1.2–28.4). After further adjustment on white matter hyperintensity volume and brain infarcts, this association remained significant for dVRS in white matter. Higher rate of cognitive decline was found to be related to high degree of dVRS in basal ganglia but not in white matter. These results need confirmation but they suggest that assessment of the severity of dVRS may help identify groups of individuals that are at increased risk of dementia. Show more

Keywords: Dilated Virchow-Robin space, incident dementia, MRI

DOI: 10.3233/JAD-2010-100378

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 663-672, 2010

Authors: Zhou, Bin | Zhao, Qianhua | Teramukai, Satoshi | Ding, Ding | Guo, Qihao | Fukushima, Masanori | Hong, Zhen

Article Type: Research Article

Abstract: We aimed to investigate the natural history of Alzheimer's disease (AD) and the risk factors associated with survival. We performed a 5-year retrospective cohort study on 467 consecutive outpatients clinically diagnosed with AD and treated between January 1, 2003, and December 31, 2006, at Huashan Hospital, Shanghai, China. The primary endpoint in this study was survival. At baseline, we evaluated the patients' demographic characteristics and neuropsychological characteristics, comorbid conditions, neuroimaging findings, complications, and neurological signs. Among the 467 patients, 398 survived. Male gender, age, and disease severity were associated with mortality. Survival analysis using the proportional hazard model with adjustments …for gender, age, and disease stage revealed that the cognition factors that predicted longer survival included high total score [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.76–0.96] and sub-scores in the verbal fluency test (animals, vegetables, and fruits). The presence of at least 1 complication was an independent factor predictive of a decreased lifespan (HR, 5.55; 95% CI, 1.91–16.13). In AD patients, presence of complications was an indicator of poor survival, while good performance in assessments of executive function, such as the verbal fluency test and Stroop test, at baseline was associated with longer survival. Show more

Keywords: Alzheimer's disease, complications, executive function, prognosis, retrospective longitudinal

DOI: 10.3233/JAD-2010-100318

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 673-682, 2010

Authors: Zhang, Can | Browne, Andrew | DiVito, Jason R. | Stevenson, Jesse A. | Romano, Donna | Dong, Yuanlin | Xie, Zhongcong | Tanzi, Rudolph E.

Article Type: Research Article

Abstract: Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-β (Aβ), a proteolytic cleavage product of amyloid-β protein precursor (AβPP). Aβ is generated through a serial cleavage of AβPP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. AβPP can also be processed by α-secretase, which cleaves AβPP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on AβPP processing and Aβ generation. …Here we assessed the effects of cell density on AβPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40 , Aβ42 , total Aβ, and the ratio of Aβ42 : Aβ40 . These results also indicate that cell density is a significant modulator of AβPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AβPP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AβPP processing and Aβ levels in the AD brain. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cell density

DOI: 10.3233/JAD-2010-100816

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 683-694, 2010

Article Type: Book Review

DOI: 10.3233/JAD-2010-100841

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 695-695, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101471

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 697-698, 2010