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Reversing Microglial Inflammarafts and Mitochondrial Dysfunction in Alzheimer's Disease

逆转阿尔茨海默病中的小胶质细胞炎症和线粒体功能障碍

基本信息

批准号：
10607455
负责人：
Mark H Ellisman
金额：
$ 78.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607455
关键词：
3-Dimensional APP-PS1 ATP binding cassette transporter 1 Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Apolipoprotein A-I Architecture Autopsy Binding Binding Proteins Bioenergetics Biological Assay Biopsy Brain Cell Death Cell Survival Cell membrane Cells Characteristics Cholesterol Cholesterol Homeostasis Chronic Development Disease associated microglia Electron Microscopy Face Flow Cytometry Genes Genus Hippocampus Goals Hippocampus Human Inflammation Inflammatory Inflammatory Response Knock-out Knockout Mice Learning Light Measures Mediating Membrane Microdomains Memory Methods Microglia Microscopic Mitochondria Morphology Mus Nerve Degeneration Oxidative Stress Pathologic Phenotype Physiological Play Proteins Role Scanning Electron Microscopy Senile Plaques Shapes Signal Transduction Site Slice Study models TLR4 gene Testing Therapeutic Transgenic Mice Variant abeta accumulation cholesterol transporters extracellular human subject improved light microscopy lipid metabolism mitochondrial dysfunction mouse model neuroinflammation neuron loss novel novel therapeutic intervention protective effect receptor recruit scaffold tau-1 tomography

项目摘要

Project Summary Neuroinflammation is a major factor in the progression of Alzheimer's disease (AD). Inflammatory brain microglia are characterized by altered cholesterol and lipid metabolism. Cholesterol and many receptors governing inflammatory responses colocalize in the ordered membrane microdomains often designated as lipid rafts. Upon activation, lipid raft resident and recruited molecules assemble and initiate signaling cascades leading to inflammation. We have identified the apoA-I binding protein (AIBP, encoded by the APOA1BP gene) as a key regulator of cellular cholesterol metabolism, which can selectively target lipid rafts in inflammatory cells (inflammarafts) via its binding to TLR4. While extracellular AIBP regulates cholesterol depletion from the plasma membrane and controls lipid rafts, intracellular AIBP localizes to mitochondria, facilitates mitophagy and helps maintain normal mitochondrial function and control oxidative stress. Apoa1bp-/- APP/PS1 mice present more amyloid beta (Aβ) plaques, an exacerbated dysfunctional microglia phenotype and show increases in cell death when compared to APP/PS1 mice. Mitochondria in AIBP-deficient microglia are morphologically distorted, with a characteristic hyper-branched and cupped shape, typically seen following oxidative stress. The AAV-mediated expression of a secreted form of AIBP in the brain of Apoa1bp-/- APP/PS1 mice restored the homeostatic microglia morphology. The goal of this proposal is to delineate mechanisms governing protective effects of AIBP in the AD brain, focusing on microglial lipid rafts and on mitochondrial dysfunction. Specifically, in Aim 1 we propose to test the hypothesis that extracellular AIBP reverses pathological lipid rafts in microglia to reduce neuroinflammation and protect against neurodegeneration in a mouse model of AD. We have identified a TLR4- binding domain in the AIBP molecule and demonstrated that an AIBP(ΔTLR4) variant, which does not bind TLR4, cannot reverse lipid raft alterations. Using AAV delivery, we plan to restore expression of secreted variants of AIBP in the brain of Apoa1bp-/- APP/PS1 mice and expect that AIBP(wt) but not AIBP(ΔTLR4) will lessen neuroinflammation, the Aβ plaque burden and accumulation of phospho-tau. We also expect improvements in memory and learning. In Aim 2, we will be testing the hypothesis that intracellular AIBP protects mitochondrial dynamics and function in a mouse model of AD. Mitochondria are the major sites displaying concentration of intracellular AIBP, and preliminary studies suggest AIBP involvement in control of mitochondrial function, mitophagy and oxidative stress. Methods will include correlated light microscopy and 3D EM across scales, leveraging advances in serial blockface scanning EM and EM tomography, along with correlated measures of bioenergetics by Seahorse. To test relevance of the proposed mechanisms to human AD, in Aim 3 we will characterize AIBP-related markers of lipid rafts and mitochondrial dysfunction in postmortem and biopsy brain sections from AD subjects.

项目总结