The new genetic landscape of Alzheimer ’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

AbstractA strong genetic predisposition (60 –80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approaches and emerging neurobio logical information, we propose an over-arching model in which the focal adhesion pathway and the related cell signalling are key elements in AD pathogenesis. The core of the focal adhesion pathway links the physiological functions of amyloid precursor protein and Tau with the pathophysiological pro cesses they are involved in. This model includes several entry points, fitting with the different origins for the disease, and supports the notion that dysregulation of synaptic plasticity is a central node in AD. Notably, our interpretation of the latest data from genome wide association studies co mplements other hypotheses already developed in the AD field, i.e., amyloid cascade, cellular phase or propagation hypotheses. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

Related Links:

Discussion of Developmental Effects on Aging Microtubule Function and Longevity in Nematodes Quantifying the Correlation Between Poverty and Faster Pace of Aging Matthew O'Connor Presenting on Underdog Pharmaceuticals at Undoing Aging 2019 https://www.fightaging.org/archives/2019/09/matthew-oconnor-presenting-on-underdog-pharmaceuticals-at-undoing-aging-2019/ Here Matthew O'Connor of the SENS Research Foundation talks about the research that led to founding of Underdog Pharmaceuticals, a biotech startup incubated by the foundation to commercialize a means of targeting 7-ketocholesterol in atheroscleros...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
CONCLUSION: Our findings suggest that although MCI subjects showed similar behavioral phenotypes at the time of diagnosis, EF and further progression were associated with different brain regions according to Aβ burden. Clarification of the etiologies and nature of EF impairment in aMCI are critical for disease prognosis and management. PMID: 31538428 [PubMed - in process]
Source: Yonsei Medical Journal - Category: Universities & Medical Training Authors: Tags: Yonsei Med J Source Type: research
IJERPH, Vol. 16, Pages 3546: New Insights on the Role of Manganese in Alzheimer’s Disease and Parkinson’s Disease International Journal of Environmental Research and Public Health doi: 10.3390/ijerph16193546 Authors: Airton Cunha Martins Patricia Morcillo Omamuyovwi Meashack Ijomone Vivek Venkataramani Fiona Edith Harrison Eunsook Lee Aaron Blaine Bowman Michael Aschner Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, a...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Review Source Type: research
CONCLUSIONS: Advance and concurrent request EAS cases differ in age, duration of illness, and past experience. Advance request EAS cases were complicated by ambiguous directives, patients being unaware of the EAS procedure, and physicians' difficulty assessing "unbearable suffering." Notably, some concurrent request patients were quite impaired yet deemed competent by appeals to previous statements. PMID: 31537470 [PubMed - as supplied by publisher]
Source: The American Journal of Geriatric Psychiatry - Category: Psychiatry Tags: Am J Geriatr Psychiatry Source Type: research
Publication date: 1 November 2019Source: Sensors and Actuators A: Physical, Volume 299Author(s): Dorsa Fahimi, Omid Mahdavipour, John Sabino, Richard M. White, Igor PaprotnyAbstractExposure to fine airborne particulate matter (PM), i.e., PM with an aerodynamic diameter (AD) less than 2.5 μm, is associated with many adverse health effects, including impaired pulmonary function, asthma, cardiovascular diseases, and Alzheimer. Consequently, there is a strong need for the development of small, low-cost wearable PM2.5 sensors that can be used by regular citizens to monitor their PM exposure. This work presents the design, ...
Source: Sensors and Actuators A: Physical - Category: Physics Source Type: research
Authors: Kim BK, Kim SA, Baek SM, Lee EY, Lee ES, Chung CH, Ahn CM, Park SK Abstract Curcumin, a compound found in Indian yellow curry, is known to possess various biological activities, including anti-oxidant, anti-inflammatory, and anti-cancer activities. Cur2004-8 is a synthetic curcumin derivative having symmetrical bis-alkynyl pyridines that shows a strong anti-angiogenic activity. In the present study, we examined the effect of dietary supplementation with Cur2004-8 on response to environmental stresses and aging using Caenorhabditis elegans as a model system. Dietary intervention with Cur2004-8 significantly...
Source: Drug Discoveries and Therapeutics - Category: Drugs & Pharmacology Tags: Drug Discov Ther Source Type: research
Source: Journal of Computational and Theoretical Nanoscience - Category: Nanotechnology Authors: Tags: research-article Source Type: research
Abstract Aim: To investigate the effect of crocin on the learning and memory acquisition of AD rats and its underlying mechanisms. Methods: A total of 48 healthy male SD rats were randomly divided into control group, AD model group, resveratrol group, and crocin group, with 12 rats per group. AD model was established by injecting Aβ 25-35 to the lateral ventricle of rats, and thereafter the rats were administrated with resveratrol (40 mg/kg), crocin (40 mg/kg), or PBS daily for 14 days. Y-maze test and sucrose preference test were used to detect the learning and memory acquisition of rats. Neuronal apopt...
Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research
Abstract Computational drug repositioning, designed to identify new indications for existing drugs, significantly reduced the cost and time involved in drug development. Prediction of drug-disease associations is promising for drug repositioning. Recent years have witnessed an increasing number of machine learning-based methods for calculating drug repositioning. In this paper, a novel feature learning method based on Gaussian interaction profile kernel and autoencoder (GIPAE) is proposed for drug-disease association. In order to further reduce the computation cost, both batch normalization layer and the full-conn...
Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research
AbstractMisfolded or unfolded proteins are accumulated in lumen of endoplasmic reticulum (ER) in ER stress condition. It has been implicated in many pathological conditions such as Alzheimer ’s disease, diabetic retinopathy, atherosclerosis, β-cell apoptosis and lung inflammation. We found a series ofN-substituted-2-arylcarbonylhydrazinecarbothioamides to potently decrease ER stress signal, showing up to almost 300-fold better activity than 1-hydroxynaphthoic acid and tauro-ursodesoxycholic acid, positive controls, respectively. Structure −activity relationship (SAR) study showed that 2-arylcarbonyl moiety...
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research
More News: Alzheimer's | Brain | Genetics | Neurology | Study | Toxicology