Current Alzheimer Research - Volume 12, Issue 8, 2015
Volume 12, Issue 8, 2015
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Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions
Authors: Joel Raskin, Jeffrey Cummings, John Hardy, Kory Schuh and Robert A. DeanBackground: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.
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Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease
Alzheimer’s disease (AD) is an aging-related multi-factorial disorder to which metabolic factors contribute at what has canonically been considered a centrally mediated process. Although the exact underlying mechanisms are still unknown, obesity is recognized as a risk factor for AD and the condition of insulin resistance seems to be the link between the two pathologies. Using mice with high fat diet (HFD) obesity we dissected the molecular mechanisms shared by the two disorders. Brains of HFD fed mice showed elevated levels of APP and Aβ40/Aβ42 together with BACE, GSK3β and Tau proteins involved in APP processing and Aβ accumulation. Immunofluorescence, Thioflavin T staining experiments, confirmed increased Aβ generation, deposition in insoluble fraction and plaques formation in both the hippocampus and the cerebral cortex of HFD mice. Presence of Aβ40/Aβ42 in the insoluble fraction was also shown by ELISA assay. Brain insulin resistance was demonstrated by reduced presence of insulin receptor (IRs) and defects in Akt-Foxo3a insulin signaling. We found reduced levels of phospho-Akt and increased levels of Foxo3a in the nuclei of neurons where proapototic genes were activated. Dysregulation of different genes related to insulin resistance, especially those involved in inflammation and adipocytokines synthesis were analyzed by Profiler PCR array. Further, HFD induced oxidative stress, mitochondrial dysfunction and dynamics as demonstrated by expression of biomarkers involved in these processes. Here, we provide evidence that obesity and AD markers besides insulin resistance are associated with inflammation, adipokine dyshomeostasis, oxidative stress and mitochondrial dysfunction, all mechanisms leading to neurodegeneration.
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Mediterranean Diet and Risk of Dementia
Dementia is a major global health challenge, as its burden on society will increase with population aging. Given the lack of effective pharmaceutical treatment for common types of dementia including Alzheimer’s disease and vascular dementia, research interest in lifestyle modifications that could prevent, postpone the clinical syndrome or decelerate progression of dementia is growing. Among the various dietary patterns that were tested for their effects on cognition, the traditional Mediterranean diet (MeDi) has shown promising results. This review aims to summarize the epidemiological evidence on the effects of MeDi on the prevention of dementia, presenting data from cross-sectional as well as longitudinal observational studies conducted both in Mediterranean and non-Mediterranean countries. These findings have been also reproduced in the context of one recent randomizedcontrolled clinical trial. Postulated mechanisms of action that may account for the potential protective effect of MeDi on cognitive impairment will be briefly discussed. Despite the fact that the link between MeDi and cognitive decline has been only explored for less than a decade, data on efficacy is rapidly increasing and allows optimism that MeDi could emerge as an alternative prophylactic treatment for dementia.
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Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer’s disease
The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson’s and Alzheimer’s disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer’s disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer’s disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer’s disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (Δex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 Δex9 mutation.
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Increased Acetylation of Histone H4 at Lysine 12 (H4K12) in Monocytes of Transgenic Alzheimer’s Mice and in Human Patients
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes. Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has been shown that aberrant epigenetic processes including acetylation are associated with the development of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12 (H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD. Methods: Mouse and human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method (Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover, monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD. Results: Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα). Conclusion: Our findings indicate that epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered as a novel biomarker for early changes in AD development.
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Anti-dementia drugs-related changes in gait performance while single and dual tasking in patients with Alzheimer disease: a meta-analysis
Authors: O. Beauchet, C. P. Launay, M Montero-Odasso, C Annweiler and G. AllaliBackground: The effects of anti-dementia drugs on gait performance in Alzheimer disease (AD) are questionable. The objective of this meta-analysis was to examine the effects of anti-dementia drugs on the mean value and the coefficient of variation (CoV) of stride time among patients with AD while taking into account the type of drugs (i.e., acetylcholinesterase inhibitors [AChEIs] versus memantine) and the walking conditions (i.e., single versus dual-task). Methods: An English and French Medline search was conducted in March 2015, with no limit of date, using the Medical Subject Headings terms “pharmaceutical preparations” combined with terms "Pharmaceutical preparations" OR "Therapeutic uses" OR "Drug substitution" OR "Drugs essential" OR "Drugs, Generic" OR "Psychotropic drugs" combined with "Delirium” OR “Dementia” OR “Amnestic” OR “Cognitive disorders" AND "Gait" OR "Gait Ataxia" OR "Gait disorders, Neurologic" OR “Gait apraxia”. Fixed-effects meta-analyses were used to examine anti-dementia drugs-related changes in mean value and CoV of stride time. Results: Of the 66 identified abstracts, 5 (7.6%) were included in the meta-analysis. Inter-group comparison of between-visit change underscored a significant decrease in CoV of stride time (P<0.004) in intervention group compared to control group, whatever the pooled analysis considered, but no significant change in the mean value (P>0.06). Intra-group changes in stride time parameters following the use of anti-dementia drugs showed a significant decrease for memantine (P<0.001) and while pooling AChEIs and memantine (P<0.001) under single task condition. Under dual task condition, only AChEIs improved significantly stride time parameters (P=0.002). Conclusion: Anti-dementia drugs demonstrated a significant improvement of gait performance with specific class effect depending on the walking conditions and on the type of stride time parameters considered.
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Long-Term Effects of Intracerebroventricular Streptozotocin Treatment on Adult Neurogenesis in the Rat Hippocampus
Altered adult hippocampal neurogenesis (AN) plays a role in the etiopathology of Alzheimer’s disease (AD), a disorder characterized by a progressive loss of memory and spatial orientation impairment. Diabetes is shown to be one risk factor for the development of the sporadic form of AD (sAD), which affects >95% of AD patients. Streptozotocin intracerebroventricularily (STZ icv) treated rats, which develop an insulin-resistant brain state and learning and memory deficits preceding amyloid beta and tau pathology, may act as an appropriate animal model for sAD. The goal of our quantitative immunohistochemistry study was to compare short-term (1 month) and long-term (3 months) effects of STZ icv treatment on different AN stages. Applying MCM2 antibodies we quantified cell (e.g. stem cell) proliferation, by the use of NeuroD and DCX antibodies we analyzed immature neurons. BrdU incorporation with approximately 27 days of survival before sacrifice allowed us to quantify and identify surviving newborn cells. Performing co-localization studies with antibodies detecting BrdU and cell-type specific markers we could confirm that STZ treatment does not affect the differentiation fate of newly generated cells. Whereas STZ icv treatment does not seem to considerably influence cell proliferation over a shortterm period (1 month), in the long-term (3 months) it significantly decreased generation of immature and mature neurons. This reduction seen after 3 months was specific for the septal hippocampus, discussed to be important for spatial learning. Moreover, AN changes display the same timeline as the development of amyloid beta pathology in this animal model of sAD.
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Mitochondrial Deficits Accompany Cognitive Decline Following Single Bilateral Intracerebroventricular Streptozotocin
Background: Bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ) causes Alzheimer’s disease (AD)-type neurodegeneration in rats. The model is increasingly used for investigating pathology and therapeutic strategies for AD. Objective: The present study investigated cognitive abilities in rats infused with STZ-ICV in relation to hippocampal and cortical mitochondrial functions during a period of 60 days. Methods: Cognitive functions were assayed in rats employing various mazes. Mitochondrial state-3-respiration, complex-I activity and dynamin related protein-1 (DRP-1) expression were measured respectively by oxygraph, spectrophotometry and immunoblot assay. Amyloidosis was investigated employing Congo red staining. Results: One-time ICV-STZ infused animals exhibited body-weight loss and impaired cognitive ability from 14th day post-infusion. A significant loss of mitochondrial electron transport chain complex-I activity in the hippocampi and cortices was found by 14 days, and persisted up to 60 days following ICV-STZ infusion. Mitochondrial state-3 respiration was unaltered in these brain regions by 14 days, but significantly decreased from 21 days after STZ administration. DRP-1 expression was significantly increased in the hippocampi and cortices of these animals 21 days after infusion, but persisted only in the hippocampi up to 60 days. Congophilic granules indicative of amyloidosis were detected in the hippocampus by 21 days. Conclusion: Our results suggest that the non-genetic sporadic AD (sAD) rat model developed by single-time STZ-ICV infusion exhibits protein aggregation and dementia probably resulting from increased mitochondrial fragmentation and functional aberrations. The present study reinforces the validity of this model for studying pathogenesis and potential therapies of sAD.
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Emotion and Destination Memory in Alzheimer’s Disease
Authors: Mohamad El Haj, Stephane Raffard, Pascal Antoine and Marie-Christine Gely-NargeotResearch shows beneficial effect of emotion on self-related information in patients with Alzheimer’s Disease (AD). Our paper investigates whether emotion improves destination memory (e.g., did I tell you about the manuscript?), which is thought to be self-related (e.g., did I tell you about the manuscript?). To this aim, twenty-seven AD patients and thirty healthy older adults told 24 neutral facts to eight neutral faces, eight positive faces, and eight negative faces. On a subsequent recognition task, participants had to decide whether they had previously told a given fact to a given face or not. Data revealed no emotional effect on destination memory in AD patients. However, in healthy older adults, better destination memory was observed for negative faces than for positive faces, and the latter memory was better than for neutral faces. The absence of emotional effect on destination memory in AD is interpreted in terms of substantial decline in this memory in the disease.
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Screening of Early and Late Onset Alzheimer’s Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy
Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer’s disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer’s and non-Alzheimer’s forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalenceof AD in the femalepopulation compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area.
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Volumes & issues
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Volume 22 (2025)
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Volume 21 (2024)
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Volume 20 (2023)
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Volume 19 (2022)
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Volume 18 (2021)
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Volume 17 (2020)
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Volume 16 (2019)
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Volume 15 (2018)
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Volume 14 (2017)
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Volume 13 (2016)
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Volume 12 (2015)
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Volume 11 (2014)
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Volume 10 (2013)
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Volume 9 (2012)
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Volume 8 (2011)
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Volume 7 (2010)
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Volume 6 (2009)
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Volume 5 (2008)
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Volume 4 (2007)
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Volume 3 (2006)
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Volume 2 (2005)
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Volume 1 (2004)
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Cognitive Reserve in Aging
Authors: A. M. Tucker and Y. Stern
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