权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defective lysosome acidification in dystrophic neurites in Alzheimer's disease contributes to failure of autophagy

阿尔茨海默病营养不良的神经突中溶酶体酸化缺陷导致自噬失败

基本信息

批准号：
10670489
负责人：
Matthew Schrag
金额：
$ 73.88万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670489
关键词：
3-Dimensional Adult Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Autophagocytosis Axon Biological Models Brain Catalytic Domain Cells Clinical Clinical Research Cognition Cognitive Cognitive aging Complex Crowding Custom Cytosol Data Data Set Defect Disease Drug Targeting Embryo Ensure Enzymes Epidemic Evaluation Failure Functional disorder Future Genes Genetic Human Hydrogels Image Impaired cognition Impairment In Vitro Individual Ions Lead Link Lysosomes Measures Mediating Membrane Memory Metabolic Methods Microscopy Molecular Molecular Target Neurites Neurobiology Neurons Organelles Outcome Pathologic Pathology Pathway interactions Pattern Peptides Point Mutation Production Proteins Proteomics RNA-Binding Proteins Regulation Research Risk Factors Role Senile Plaques Slice Structure Techniques Ubiquitination Variant Work base cell injury data streams design drug development drug discovery druggable target effective therapy genetic risk factor golgin human model in vitro Model induced pluripotent stem cell loss of function molecular drug target mouse model neuropathology next generation novel pre-clinical protein aggregation proteostasis religious order study risk variant tau Proteins tau aggregation transcriptome sequencing transcriptomics vacuolar H+-ATPase

项目摘要

Alzheimer’s disease is a national crisis and the burden of this terrible disease is rising. After decades of failure to produce a disease modifying treatment for Alzheimer’s disease, it is critical that we identify drug targets that are linked to causal mechanisms underlying the diverse neuropathological substrates of Alzheimer’s disease. Our research focuses on the function of lysosomes within an axonal structure called a dystrophic neurite. Dystrophic neurites form when axon segments pass near a β-amyloid plaque and become distended and clogged with lysosomes and related organelles. Tau aggregates are also present in some dystrophic neurites, so this pathology seems to link the major pathological hallmarks of Alzheimer’s disease. Because lysosomes are critical for protein homeostasis, we hypothesize that loss of function of these lysosomes is a key step in the formation of toxic protein aggregates. We demonstrated a pattern of changes in the function this pool of lysosomes which could be explained by failure of acidification, so in this proposal we will evaluate 1) whether lysosomes in dystrophic neurites are able to acidify and what molecular mechanisms may underlie failed acidification, 2) whether loss of lysosome acidification results in defective autophagy and accumulation of pathologic autophagic intermediates within dystrophic neurites and 3) the degree to which a novel Alzheimer’s disease genetic risk factor, RBFOX1, contributes to altered autophagy and pH regulation in neuronal lysosomes. For each of these aims, we leverage advanced in vitro methods including organotypic brain slice cultures from adult model animals and three-dimensional human neuronal cultures derived from induced pluripotent stem cells grown in a custom designed hydrogel matrix. Using live-imaging, we will quantitatively measure the pH in lysosomes in dystrophic neurites. We will conduct detailed neuropathological studies simultaneously in human and mouse model systems to identify altered distribution of vacuolar ATPase subunits, ARL1 and Golgin A4 which are key regulators of autophagy, and RBFOX1. Additionally, we want to understand the cognitive and neuropathological associations of each component of the molecular pathways that contribute to failed acidification, defective autophagy and tau aggregation, so we will leverage RNAseq and proteomic data from large clinical studies, in particularly the Religious Orders Study/Memory and Alzheimer’s Project, to ensure these pathways are functionally important. These synergistic streams of data will converge to robustly establish the mechanism and consequence of loss of lysosome acidification in dystrophic neurites and identify molecular targets for future drug discovery efforts.

阿尔茨海默病是一场全国性的危机，这种可怕疾病的负担正在上升。后