Journal of Alzheimer's Disease - Volume 19, issue 4

Authors: Li, Yazhou | Duffy, Kara B. | Ottinger, Mary Ann | Ray, Balmiki | Bailey, Jason A. | Holloway, Harold W. | Tweedie, David | Perry, TracyAnn | Mattson, Mark P. | Kapogiannis, Dimitrios | Sambamurti, Kumar | Lahiri, Debomoy K. | Greig, Nigel H.

Article Type: Research Article

Abstract: Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures …and on amyloid-β protein (Aβ) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Aβ and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Aβ protein precursor and Aβ, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance. Show more

Keywords: 3xTg-AD mice, Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, dementia, diabetes, extendin-4, glucagon-like peptide-1, neuroprotection, streptozocin, tau

DOI: 10.3233/JAD-2010-1314

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1205-1219, 2010

Authors: Qian, Wei | Shi, Jianhua | Yin, Xiaomin | Iqbal, Khalid | Grundke-Iqbal, Inge | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in Alzheimer's disease (AD). Previous studies suggest that a down-regulation of protein phosphatase 2A (PP2A), the major tau phosphatase in human brain, contributes to tau hyperphosphorylation in AD. However, the effects of PP2A down-regulation on site-specific tau hyperphosphorylation is not well understood. In the present study, we showed that PP2A dephosphorylated tau at several phosphorylation sites with different efficiencies. Among the sites studied, Thr205, Thr212, Ser214, and Ser262 were the most favorable sites, and Ser199 and Ser404 were the least favorable sites for PP2A in vitro. Inhibition of PP2A …with okadaic acid in metabolically active rat brain slices caused inhibition of glycogen synthase kinase-3β (GSK-3β) via an increase in its phosphorylation at Ser9. GSK-3β phosphorylated tau at many sites, with Ser199, Thr205, and Ser396 being the most favorable sites in cells. The overall alterations in tau phosphorylation induced by PP2A inhibition were the result of the combined effects of both reduced tau dephosphorylation due to PP2A inhibition directly and reduced phosphorylation by GSK-3β due to its inhibition. Because the impacts of tau phosphorylation on its biological activity and on neurofibrillary degeneration are site-specific, this study provides a new insight into the role of PP2A down-regulation in neurofibrillary degeneration in AD. Show more

Keywords: GSK-3β, phosphorylation, PP2A, tau

DOI: 10.3233/JAD-2010-1317

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1221-1229, 2010

Authors: Lee, Soon-Tae | Chu, Kon | Jung, Keun-Hwa | Jeon, Daejong | Bahn, Jae-Jun | Kim, Jin-Hee | Kun Lee, Sang | Kim, Manho | Roh, Jae-Kyu

Article Type: Research Article

Abstract: Vascular senescence contributes to the progression of Alzheimer's disease (AD) and circulating angiogenic cells (CACs) participate in the maintenance of the endothelium. As a step toward the development endothelial regeneration therapies for AD, we investigated the functional characteristics of CACs in AD patients. We enrolled AD patients and non-demented risk factor control subjects after matching for age, sex, and Framingham risk score. CACs were cultured from peripheral blood samples taken from subjects and used for various ex vivo assays. CACs from AD patients showed reduced chemotaxis, increased senescence, reduced paracrine angiogenic activity, and altered gene expression patterns compared to CACs …from risk factor (RF) controls. Addition of high concentration Aβ1–42 (200, 2000 ng/mL) to the CAC culture reduced CAC counts and endothelial nitric oxide synthase/Akt phosphorylation and induced apoptosis. However, lower concentration of Aβ1–42 (2, 20 ng/mL) failed to reduce the CAC counts. CACs from AD patients were more susceptible to the cytotoxic effect of Aβ1–42 than CACs from RF controls. In summary, AD patients have intrinsic dysfunctions of CACs which provides an extended understanding of vascular endothelial pathogenesis in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, angiogenesis, circulating angiogenic cells, endothelial

DOI: 10.3233/JAD-2010-1315

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1231-1240, 2010

Authors: Sadowski, Martin J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-01343

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1241-1243, 2010

Authors: Perucho, Juan | Rubio, Isabel | Casarejos, Maria J. | Gomez, Ana | Rodriguez-Navarro, Jose A. | Solano, Rosa M. | De Yébenes, Justo Garcia | Mena, Maria A.

Article Type: Research Article

Abstract: There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer's disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on “in vitro” experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-β (Aβ) peptide and tau patterns, chaperones and autophagy in WT and …AβPPswe mice. We have found that AβPPswe mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL+ apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased Aβ aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with increased susceptibility but does not affect normal subjects. Show more

Keywords: AβPPswe mice, amyloid pathology, apoptotic cell death, autophagy, chaperones, cognitive deficits, glial cells, isoflurane

DOI: 10.3233/JAD-2010-1318

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1245-1257, 2010

Authors: Eckenhoff, Maryellen F. | Eckenhoff, Roderic G.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-1324

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1259-1260, 2010

Authors: Perucho, Juan | Rubio, Isabel | Casarejos, Maria J. | Gomez, Ana | Rodriguez-Navarro, Jose A. | Solano, Rosa M. | De Yébenes, Justo Garcia | Mena, Maria A.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-1325

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1261-1261, 2010

Authors: Oliveira Jr., Pedro Paulo de Magalhães | Nitrini, Ricardo | Busatto, Geraldo | Buchpiguel, Carlos | Sato, João Ricardo | Amaro Jr., Edson

Article Type: Research Article

Abstract: Here, we examine morphological changes in cortical thickness of patients with Alzheimer's disease (AD) using image analysis algorithms for brain structure segmentation and study automatic classification of AD patients using cortical and volumetric data. Cortical thickness of AD patients (n = 14) was measured using MRI cortical surface-based analysis and compared with healthy subjects (n = 20). Data was analyzed using an automated algorithm for tissue segmentation and classification. A Support Vector Machine (SVM) was applied over the volumetric measurements of subcortical and cortical structures to separate AD patients from controls. The group analysis showed cortical thickness reduction in the …superior temporal lobe, parahippocampal gyrus, and enthorhinal cortex in both hemispheres. We also found cortical thinning in the isthmus of cingulate gyrus and middle temporal gyrus at the right hemisphere, as well as a reduction of the cortical mantle in areas previously shown to be associated with AD. We also confirmed that automatic classification algorithms (SVM) could be helpful to distinguish AD patients from healthy controls. Moreover, the same areas implicated in the pathogenesis of AD were the main parameters driving the classification algorithm. While the patient sample used in this study was relatively small, we expect that using a database of regional volumes derived from MRI scans of a large number of subjects will increase the SVM power of AD patient identification. Show more

Keywords: Alzheimer's disease, FreeSurfer, magnetic resonance imaging, support vector machine, surface based methods

DOI: 10.3233/JAD-2010-1322

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1263-1272, 2010

Authors: Cherubini, Andrea | Péran, Patrice | Spoletini, Ilaria | Di Paola, Margherita | Di Iulio, Fulvia | Hagberg, Gisela Elizabeth | Sancesario, Giuseppe | Gianni, Walter | Bossù, Paola | Caltagirone, Carlo | Sabatini, Umberto | Spalletta, Gianfranco

Article Type: Research Article

Abstract: The aim of this work was to investigate the hypothesis that multimodal MRI is able to detect the progressive disruption of volume and microstructure of subcortical structures in patients with amnestic mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD) in comparison with healthy controls (CTRL). We combined volumetric and diffusion tensor imaging (DTI) techniques in a cross-sectional study including 30 a-MCI, 30 AD patients, and 30 age-matched CTRL. We employed a fully automated model-based segmentation algorithm on 3 Tesla MRI anatomical images and accurate coregistration of DTI to anatomical images to extract regional values of DTI parameters. Both the …hippocampi significantly and progressively decreased in volume from CTRL through MCI to AD. Both the thalami showed a progressive and significant decrease in volume from CTRL to AD. Mean diffusivity (MD) values increased progressively across the three groups in the bilateral hippocampus, amygdala, and in the right caudate. No differences in fractional anisotropy (FA) values were found. Two distinct but overlapping patterns of progression of structural (i.e., atrophy) and microstructural (i.e., MD increase) damage were observed. Particularly, the pattern of atrophy was mirrored by the increasing value of the averaged MD, which provided a further indicator of subtle tissue disruption in the hippocampal structure in mild AD patients. Combining different MRI modalities can allow identifying sensitive indicators of the subtle pathogenic mechanisms that occur in subcortical areas of AD patients. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging, mild cognitive impairment, MRI, subcortical areas

DOI: 10.3233/JAD-2010-091186

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1273-1282, 2010

Authors: Xin, Xiao-Yu | Ding, Jian-Qing | Chen, Sheng-Di

Article Type: Research Article

Abstract: Apolipoprotein E (APOE) promoter polymorphisms have long been linked to Alzheimer disease (AD) susceptibility, although the established data remains controversial. Using meta-analysis, our study aimed to clarify the nature of the genetic risks contributed by the three polymorphisms for developing AD. Medline, Embase, and Alzgene search identified 40 studies with 9,662 cases and 9.696 controls. Both -491A/T polymorphism (AA vs AT + TT: OR = 1.49, 95% CI = 1.29–1.72) and -219T/G polymorphism (TT vs TG + GG: OR = 1.30, 95% CI = 1.10–1.55) showed a significant association with AD susceptibility; however, significant association was not identified in the …analysis for -427T/C polymorphism (TT vs TC + CC: OR = 1.03, 95% CI = 0.82–1.30). Among the APOE ε 4} carriers, the -491A homozygotes were at higher risk to develop AD compared with the -491T carriers (OR = 1.42, 95% CI = 1.15–1.76). For subjects carrying the -491AA genotype, the presence of the APOE ε4 allele increased the risk of AD 4.37-fold (95% CI = 3.43–5.56). Subgroup analysis restricted to the late-onset or the Caucasian individuals revealed a similar association as that identified without restriction regarding -491A/T polymorphism. Our results confirm a significant but modest association between APOE promoter -491A/T and -219T/G polymorphisms and AD susceptibility. Show more

Keywords: Alzheimer's disease, APOE promoter, meta-analysis, -491A/T, -427T/C, -219T/G

DOI: 10.3233/JAD-2010-1329

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1283-1294, 2010