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.
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.