β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.

ABSTRACT: Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. β-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with β-arrestin2^-/- mice, show that β-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms. Genetic ablation of β-arrestin2 markedly ablates tau

SUBMITTER: Woo JA 

PROVIDER: S-EPMC7060747 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature