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Temporal and spatial aspects of amyloidogenesis in sporadic Alzheimer disease

散发性阿尔茨海默病淀粉样蛋白生成的时间和空间方面

基本信息

批准号：
10297726
负责人：
MALCOLM A LEISSRING
金额：
$ 58.35万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297726
关键词：
ABCB1 gene Abeta clearance Abeta synthesis Address Age Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Animals Aspartic Endopeptidases Basic Science Blood - brain barrier anatomy Brain Cathepsins Cells Cerebrum Chronic Clinical Clinical Trials DNA Sequence Alteration Data Defect Deposition Development Diffuse Disease Down-Regulation Early Diagnosis Elderly Environment Etiology Exploratory/Developmental Grant for Diagnostic Cancer Imaging Genetic Goals Grant Human Impairment Innovative Therapy Knock-in Mouse Lead Life Link Memory Loss Methods Modeling Mus Mutation Neprilysin Nerve Degeneration Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathology Peptide Hydrolases Play Proteins Risk Factors Role Senile Plaques Stress Study models Symptoms Tariquidar Testing Time Traumatic Brain Injury Twin Multiple Birth Work abeta deposition age related aged amyloidogenesis effective therapy experimental study extracellular familial Alzheimer disease human old age (65+)improved inhibitor/antagonist innovation insight interest mouse model novel poor sleep promoter therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Rare forms of familial Alzheimer disease (fAD) are known to be caused by life-long, genetically determined perturbations in the production of the amyloid ß-protein (Aß), but the cause(s) of the vast majority of so-called sporadic AD (sAD) cases remains remarkably poorly defined. This proposal will use state-of-the-art mouse models of sAD together with several highly innovative approaches to address key temporal and spatial aspects of sAD pathogenesis for the first time, with critical implications for the development of effective therapies. Whereas fAD is attributable to chronic perturbations in the production of Aß, we hypothesize that sAD is triggered by impairments in the clearance of Aß—specifically by transient impairments in Aß clearance. This hypothesis is consistent with evidence showing that several established risk factors for sAD, such as brain trauma, stress, or poor sleep, lead to short-lived or episodic increases in cerebral Aß levels due to reduced Aß clearance. To model this novel mechanistic hypothesis, we employ innovative methods to inhibit Aß clearance transiently and reversibly by blocking either blood-brain barrier transport of Aß or its proteolytic degradation. Because we aim to define the triggers for sAD, we require an animal model that does not develop AD-type pathology on its own, as most AD mouse models do. To this end, we will use an innovative new sAD mouse model, the APPNL-F/hAß mice, which expresses wild-type human Aß only, under the control of the endogenous murine App promoter, with the minimal genetic mutations needed to model sAD. As is true for normal humans, this sAD mouse model develops diffuse deposits of human Aß in an age-dependent manner, and forms very minimal dense-core plaques only at very advanced ages. Accordingly, these mice are ideal for investigating the pathophysiological mechanisms responsible for triggering the conversion of “normal” Aß deposition to the pathological type in sAD. We hypothesize further that the Aß-dependent pathological mechanisms most relevant to sAD occur much earlier than the ages studied in clinical trials, with clinical symptoms emerging only much later, specifically in the context of aging. Accordingly, we will define the temporal window most relevant to the emergence of AD by increasing Aß levels in APPNL-F/hAß mice transiently at various ages, then evaluating the consequences for the development of AD-type pathology longitudinally, up to and including old age. Finally, we will test the novel hypothesize that spatially distinct pools of Aß (e.g., extra- vs. intracellular) impact the pathogenesis of AD in qualitatively different ways. Specifically, we postulate that intracellular Aß is more relevant than extracellular Aß to the neurodegeneration and memory loss that characterize AD. To test this, we will selectively increase extra- vs. intracellular pools of Aß by reversibly downregulating Aß-degrading proteases that, as our preliminary results show, selectively regulate these distinct pools of Aß. Collectively, these experiments will allow us to investigate, cleanly and for the first time, many critical temporal and spatial aspects of AD pathogenesis, yielding novel insights that will inform improved approaches to the treatment of sAD.

项目总结/文摘