β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy.

Life Science Alliance
Jung-Aa WooDavid E Kang

Abstract

G protein-coupled receptors (GPCRs) have been shown to play integral roles in Alzheimer's disease pathogenesis. However, it is unclear how diverse GPCRs similarly affect Aβ and tau pathogenesis. GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events. As signaling via the GPCRs, β2-adrenergic receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2) promotes hyperphosphorylation of tau, we hypothesized that β-arrestin1 represents a point of convergence for such pathogenic activities. Here, we report that β-arrestins are not only essential for β2AR and mGluR2-mediated increase in pathogenic tau but also show that β-arrestin1 levels are increased in brains of Frontotemporal lobar degeneration (FTLD-tau) patients. Increased β-arrestin1 in turn drives the accumulation of pathogenic tau, whereas reduced ARRB1 alleviates tauopathy and rescues impaired synaptic plasticity and cognitive impairments in PS19 mice. Biochemical and cellular studies show that β-arrestin1 drives tauopathy by destabilizing microtubules and impeding p62/SQSTM1 autophagy flux by interfering with p62 body ...Continue Reading

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