The major defining pathological hallmarks of Alzheimer?s disease (AD) are the accumulation of amyloid ? (A?) and hyperphosphorylated tau. Multiple GPCRs (i.e, ?2AR, 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 A? and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via ?-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of ?-arrestins downstream of GPCRs directly impact AD pathogenesis. ?-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 ?-arrestins are upregulated in AD brains and that ?- arrestins promote A? pathogenesis. However, it is unknown whether and how ?-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that ?-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 ?-arrestins in tauopathy in vivo, 2) validate the role of ?-arrestins in tau/microtubule dynamics, and 3) investigate the role of ?- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether ?- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.

Public Health Relevance

Tau pathology (tauopathy) is a prevailing hallmark of Alzheimer?s disease (AD) and multiple other neurodegenerative diseases. This proposal aims to understand how ?-arrestins, proteins known to regulate various neuronal signaling receptors (GPCRs), contribute to tauopathy in brain. This proposal will allow us to determine whether ?-arrestins and their conformational states serve as promising therapeutic targets to mitigate tau pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG059721-03
Application #
10094176
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2019-05-15
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33617