β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.
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 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.
['Woo|Jung-A A|JA|', 'Liu|Tian|T|', 'Fang|Cenxiao C|CC|', 'Castaño|Maria A|MA|', 'Kee|Teresa|T|', 'Yrigoin|Ksenia|K|', 'Yan|Yan|Y|', 'Cazzaro|Sara|S|', 'Matlack|Jenet|J|', 'Wang|Xinming|X|', 'Zhao|Xingyu|X|', 'Kang|David E|DE|', 'Liggett|Stephen B|SB|']
D000544:Alzheimer Disease D000818:Animals D001343:Autophagy D001921:Brain D004195:Disease Models, Animal D057180:Frontotemporal Dementia D057174:Frontotemporal Lobar Degeneration D051379:Mice D018345:Mice, Knockout D008822:Mice, Transgenic D009474:Neurons D059467:Transcriptome D000071560:beta-Arrestin 2 D016875:tau Proteins
β-arrestin2 tau autophagy tauopathies Alzheimer’s disease