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Novel role of β-arrestins in Tauopathy

β-抑制蛋白在 Tau 病中的新作用

基本信息

批准号：
10094176
负责人：
JungA Alexa Woo
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094176
关键词：
Abeta synthesis Ablation Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Arrestins Autophagocytosis Autophagosome Axon Axonal Transport Behavioral Binding Biochemical Biological Brain Cells Complex Data Defect Deposition Distal Electrophysiology (science)Future G-Protein-Coupled Receptors GPR3 gene Genetic IL8RB gene Impaired cognition Impairment In Vitro Learning Link Lysosomes Measures Mediating Memory impairment Microfluidic Microchips Microtubule Depolymerization Microtubules Mitochondria Modeling Molecular Molecular Conformation Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Play Proteins Receptor Signaling Recombinant adeno-associated virus (rAAV)Recovery of Function Reporter Role Signal Transduction Solid Synapses Synaptic plasticity Tauopathies Testing Therapeutic Transgenic Mice Viral abeta accumulation base beta-arrestin desensitization gamma secretase hyperphosphorylated tau in vivo indexing insight interdisciplinary approach neuroinflammation neuronal cell body neurotransmission novel receptor binding receptor internalization retrograde transport scaffold tau Proteins therapeutic target tool trafficking

项目摘要

The major defining pathological hallmarks of Alzheimer’s disease (AD) are the accumulation of amyloid β (Aβ) and hyperphosphorylated tau. Multiple GPCRs (i.e, β2AR, GPR3, AT2R, CXCR2, & NMDARs) have been shown to play integral roles in AD pathogenesis. However, it is unclear as to how a diverse array of GPCRs all positively impinge on Aβ and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via β-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of β-arrestins downstream of GPCRs directly impact AD pathogenesis. β-arrestins exist in three distinct states in cells; 1) free unbound, 2) GPCR-bound, and 3) microtubule-bound, each with different signaling capability. Previous studies have shown that β-arrestins are upregulated in AD brains and that β- arrestins promote Aβ pathogenesis. However, it is unknown whether and how β-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that β-arrestin oligomers promote tauopathy via 2 distinct mechanisms: 1) directly competing with tau for binding to microtubules (MT), thereby deregulating MT dynamics; 2) inhibiting tau clearance by deregulating the autophagy machinery. By utilizing molecular, cell biological, biochemical, electrophysiological, behavioral, viral, and histochemical tools, this proposal will 1) validate the role of β-arrestins in tauopathy in vivo, 2) validate the role of β-arrestins in tau/microtubule dynamics, and 3) investigate the role of β- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether β- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.

阿尔茨海默病（AD）的主要病理标志是