Journal of Alzheimer's Disease - Volume 25, issue 1

Authors: Neumann, Karen | Farías, Gonzalo | Slachevsky, Andrea | Perez, Patricio | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Platelets are a major peripheral reservoir of the amyloid-β protein precursor, so they have been considered as a potential biological marker of Alzheimer's disease (AD). Here, it is demonstrated that tau protein is also present in platelets and that the levels of oligomeric species of this protein could serve as a novel and reliable biological marker for AD. Blood samples were obtained from 15 AD patients and 10 paired-age controls and platelets were separated via differential centrifugation. The purity of platelets was determined by flow cytometry and microscopy and the presence of tau was determined by immunofluorescence and immunoblots with …tau specific antibodies. Immunofuorescence and immunoblot patterns of platelets were positive for tau. Immunoblots also showed the presence of high molecular weight (HMW) variants of tau that appeared to correspond to oligomeric forms of the protein. The ratio of HMW tau respect to tau monomeric species was significantly higher in AD patients than controls. The present is the first description of the presence of tau in platelets. The analysis of different tau fractions in platelets could serve as a new biological marker for AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, human platelets, molecular biomarkers, protein self aggregation, tau proteins

DOI: 10.3233/JAD-2011-101641

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 103-109, 2011

Authors: Li, Hong-Lei | Shi, Sheng-Sheng | Guo, Qi-Hao | Ni, Wang | Dong, Yi | Liu, Ying | Sun, Yi-Min | Bei-Wang, | Lu, Shen-Ji | Hong, Zhen | Wu, Zhi-Ying

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of senile dementia, and the overall prevalence increases exponentially with age. It is well known that genetic variants may play an important role in the pathogenesis of this disorder. Recently, two independent large-scale genome-wide association studies (GWAS) identified 3 novel single nucleotide polymorphisms (SNPs) (rs11136000 within CLU, rs3851179 within PICALM and rs6656401 within CR1) that are associated with late-onset AD (LOAD), and these results have been replicated by other studies performed in the Caucasian population. Recently, an independent study failed to verify the association for the SNP within CLU in a Han …Chinese population, indicating that there may be genetic heterogeneity in this association. In the present study, we studied the SNPs within PICALM and CR1 in 474 sporadic AD patients (SAD) and 591 unrelated age- and sex-matched healthy controls of Han Chinese descent. Our data revealed that the frequencies of both of these SNPs were not significantly difference between the SAD and control groups. Thus, the association between SNPs within PICALM, CR1, and SAD should be studied further in different ethnic groups. Show more

Keywords: Alzheimer's disease, Chinese, CR1, PICALM

DOI: 10.3233/JAD-2011-101917

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 111-117, 2011

Authors: Schlatterer, Sarah D. | Tremblay, Matthew A. | Acker, Christopher M. | Davies, Peter

Article Type: Research Article

Abstract: Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKIIα) regulated by doxycycline (Tet-Off). …Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis. In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease. Show more

Keywords: Alzheimer's disease, Arg, c-Abl, gliosis, neurodegeneration, transgenic

DOI: 10.3233/JAD-2011-102025

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 119-133, 2011

Authors: Fiala, Milan | Mahanian, Michelle | Rosenthal, Mark | Mizwicki, Matthew T. | Tse, Eric | Cho, Tiffany | Sayre, James | Weitzman, Rachel | Porter, Verna

Article Type: Research Article

Abstract: Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-β 1-42 (Aβ) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aβ phagocytosis. The transcription of MGAT3 stimulated by Aβ distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 …transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aβ in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aβ. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study. Show more

Keywords: Alzheimer's disease, amyloid-β, MGAT3, surgical anesthesia, vitamin D3

DOI: 10.3233/JAD-2011-101950

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 135-144, 2011

Authors: Wu, Ya-Ying | Cheng, Irene Han-Juo | Lee, Chin-Cheng | Chiu, Ming-Jang | Lee, Ming-Jen | Chen, Ta-Fu | Hsu, Jung-Lung

Article Type: Research Article

Abstract: Familial Alzheimer's disease (FAD) is genetically heterogeneous, autosomal dominant, with nearly 100% penetrance. In FAD, most common causative genetic mutations are presenilin 1 (PSEN1), presenilin 2 and amyloid-β protein precursor. We demonstrate a family presenting as early-onset AD with a rapid deterioration course and seizure developed after 1.5 years of symptoms. A histopathological examination of the frontal cortex showed amyloid deposition and abundant phosphorylated tau deposition. In both cases, a single nucleotide mutation from guanine to adenine at exon 7 was found in PSEN1 (c.617G>A, codon change from GGT to GAT). Though G206D mutation in PSEN1 gene was found in …FAD, no clinical phenotype or pathological finding was documented. This is the first report of PSEN1 mutation (Gly206Asp) with features of seizure and a rapid progressive cognitive decline in a pathologically confirmed case of FAD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, epilepsy, presenilin 1 (PSEN1), tau protein

DOI: 10.3233/JAD-2011-102031

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 145-150, 2011

Authors: Katsouri, Loukia | Parr, Callum | Bogdanovic, Nenad | Willem, Michael | Sastre, Magdalena

Article Type: Research Article

Abstract: We have previously reported that the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) regulates the transcription of β-secretase (BACE1), a key enzyme involved in amyloid-β (Aβ) generation. Here, we aimed to investigate the role of PPARγ coactivator-1α (PGC-1α), which controls major metabolic functions through the co-activation of PPARγ and other transcription factors. Western blotting experiments with nuclear extracts from brain cortex of AD cases and controls showed a reduction in the levels of PGC-1α in AD patients. PGC-1α overexpression in N2a neuroblastoma cells induced a decrease in the levels of secreted Aβ and an increase in the levels of non-amyloidogenic …soluble AβPPα. The decrease in Aβ after exogenous expression of PGC-1α was a consequence of reduced BACE1 expression and transcription, together with a decrease in BACE1 promoter activity. In addition, we detected a significant reduction in β-secretase activity by measuring the levels of β-carboxy terminus fragment (β-CTFs) and by using a commercial assay for β-secretase. In contrast, down-regulation of PGC-1α levels by transfection with PGC-1α siRNA increased BACE1 expression. These effects appeared to be dependent on PPARγ, because PGC-1α did not affect Aβ and BACE1 levels in N2a cells transfected with PPARγ siRNA or in PPARγ knockout fibroblasts. In conclusion, since PGC-1α appears to decrease Aβ generation, therapeutic modulation of PGC-1α could have real potential as a treatment for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, BACE1, neprilysin, PGC-1α, PPARγ

DOI: 10.3233/JAD-2011-101356

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 151-162, 2011

Authors: Trittschuh, Emily H. | Crane, Paul K. | Larson, Eric B. | Cholerton, Brenna | McCormick, Wayne C. | McCurry, Susan M. | Bowen, James D. | Baker, Laura D. | Craft, Suzanne

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is proposed to be a prodrome to dementia in some older adults. However, the presentation of MCI in the community can differ substantially from clinic-based samples. The aim of the current study is to demonstrate the effects of different operational definitions of MCI on prevalence estimates in community-dwelling older adults. A consecutive series of 200 participants aged 65 and over from the Adult Changes in Thought (ACT) community-based cohort were approached to undergo comprehensive neuropsychological and medical evaluation; 159 were included in the final analyses. Nondemented subjects were categorized using various diagnostic criteria for MCI. In …a novel approach, neuropsychological test scores were evaluated using an individualized benchmark as a point of test comparison, as well as traditional methods that entail comparison to age-based normative data. Diagnostic criteria were further subdivided by severity of impairment (1.0 vs. 1.5 standard deviations [sd] below the benchmark) and extent of impairment (based on a single test or an average of tests within a cognitive domain). MCI prevalence rates in the sample were highly dependent on these diagnostic factors, and varied from 11% to 92% of the sample. Older groups tended to show higher prevalence rates, although this was not the case across all diagnostic schemes. The use of an individualized benchmark, less severe impairment cutoff, and impairment on only a single test all produced higher rates of MCI. Longitudinal follow-up will determine whether varying diagnostic criteria improves sensitivity and specificity of the MCI diagnosis as a predictor for dementia. Show more

Keywords: Age-related memory disorders, aging, Alzheimer's disease, cognition, dementia, diagnosis, epidemiology, individual differences, neuropsychological tests, normative, prevalence

DOI: 10.3233/JAD-2011-101821

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 163-173, 2011

Authors: Martin, George M.

Article Type: Book Review

DOI: 10.3233/JAD-2011-110120

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 175-176, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-101822

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 177-178, 2011