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Synpatic Autophagy in Alzheimer Disease

阿尔茨海默病中的突触自噬

基本信息

批准号：
9141011
负责人：
RICHARD J REIMER
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9141011
关键词：
Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Autophagocytosis Award Axon Behavioral Binding Brain Catabolism Cause of Death Cells Clinical Cognitive Data Dementia Dendrites Deposition Deterioration Diagnosis Disease Disease Progression Disease model Down-Regulation Economic Burden Elderly Endoplasmic Reticulum Enhancers Excision Exocytosis Family Fluorescence Microscopy Functional disorder Genetic study Health Hippocampus (Brain)Histopathology Image Impaired cognition Impairment In Situ Nick-End Labeling In Vitro Individual Knowledge Lentivirus Vector Link Lysosomes MAPT gene Maintenance Measures Mediating Mitochondria Molecular Molecular Target Mouse Protein Nerve Degeneration Neurodegenerative Disorders Neurons Organelles PHluorin Pathologic Pathology Peptides Pharmacology Phosphorylation Pilot Projects Play Population Presynaptic Terminals Process Proteins Quality Control Recombinant Proteins Regulation Role Scaffolding Protein Senile Plaques Site Societies Staining method Stains Structure Synapses Synaptic Vesicles Synaptophysin System Testing Therapeutic Traumatic Brain Injury Veterans Work abeta deposition abeta oligomer base bassoon protein cognitive ability cognitive function disability experimental study extracellular immunoreactivity in vitro Model in vivo Model mouse model multicatalytic endopeptidase complex neurofibrillary tangle formation neuron loss neuronal survival neurotoxicity new therapeutic target novel peroxisome presynaptic programs progressive neurodegeneration protein aggregate proteostasis public health relevance response social symptom treatment synaptic function tau Proteins therapeutic development tool vector

项目摘要

DESCRIPTION (provided by applicant): Alzheimer disease (AD) produces a progressive degeneration of the brain that slowly destroys a victim's cognitive abilities. This disease inflicts tremendous social and economic burden on families and society in general. It is projected that more than 200,000 Veterans will be diagnosed with dementia in 2017, with AD the most common cause. Therapeutic options for AD remain very limited and no treatments have been shown to slow the relentless progression of the disease. Pathologically AD is characterized by the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) and the abnormal phosphorylation of the microtubule associated protein tau that results in the formation of tangles inside neurons. These protein deposits are associated with a dramatic loss of neurons in the cortex and hippocampus. The mechanistic relationship between these protein accumulations and neurodegeneration is, however, unknown. Synaptic dysfunction and loss of axon terminals are among the earliest recognized changes in AD, suggesting that impairment of mechanisms that maintain integrity of synapses may underlie or contribute to pathology. Removal and replacement of damaged proteins (proteostasis) is a primary mechanism by which cells maintain functional structures such as mitochondria. Clearance is mediated by two interconnected systems-the ubitquitin-proteasome system and the autophagy-lysosome system. Interestingly, recent studies indicate that there may be locally regulated proteostasis programs at presynaptic terminals. In our preliminary data we demonstrate that the autophagy-lysosome system is upregulated specifically at synapses in response to Aβ. In this Pilot Project we propose to test the hypothesis that presynaptic autophagy plays a crucial role in the neurodegeneration that occurs in AD. To test the hypothesis, we have generated two presynaptically targeted molecular regulators of autophagy - one enhancer and one suppressor. We propose to determine the consequences of altering presynaptic autophagy on an in vitro model of AD as well as a murine model of the disease. At the end of the proposed studies we expect to have a better understanding of autophagy of presynaptic structures and how this process relates to neurodegeneration in AD. This knowledge will hopefully help us to identify novel targets for the treatments that slow the progress of this devastating disease.