β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates
Jung A. Woo, Tian Liu, Cenxiao Fang, Maria A. Castaño, Teresa R. Kee, Ksenia Yrigoin, Yan Yan, Sara Cazzaro, Jenet Matlack, Xinming Wang, Xingyu Zhao, David E. Kang, Stephen B. Liggett
Abstract
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 pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, β-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized β-arrestin2 with virus encoding β-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing β-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.