Thursday, April 25, 2024
4/25/2024
The major defining pathological hallmarks of Alzheimer’s disease (AD) are the accumulation of amyloid ß (Aß) and hyperphosphorylated tau. Multiple GPCRs (i.e, ß2AR, 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 Aß and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via ß-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of ß-arrestins downstream of GPCRs directly impact AD pathogenesis. ß-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 ß-arrestins are upregulated in AD brains and that ß- arrestins promote Aß pathogenesis. However, it is unknown whether and how ß-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that ß-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 ß-arrestins in tauopathy in vivo, 2) validate the role of ß-arrestins in tau/microtubule dynamics, and 3) investigate the role of ß- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether ß- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
