Abstract

Haploinsufficiency for the p53 family member p73 causes behavioral and neuroanatomical correlates of neurodegeneration in aging mice, including the appearance of aberrant phospho-tau-positive aggregates. Here, we show that these aggregates and tau hyperphosphorylation, as well as a generalized dysregulation of the tau kinases GSK3 beta, c-Abl, and Cdk5, occur in the brains of aged p73+/- mice. To investigate whether p73 haploinsufficiency therefore represents a general risk factor for tau hyperphosphorylation during neurodegeneration, we crossed the p73+/- mice with 2 mouse models of neurodegeneration, TgCRND8+/empty set mice that express human mutant amyloid precursor protein, and Pin1-/- mice. We show that haploinsufficiency for p73 leads to the early appearance of phospho-tau-positive aggregates, tau hyperphosphorylation, and activation of GSK3 beta, c-Abl, and Cdk5 in the brains of both of these mouse models. Moreover, p73+/-; TgCRND8+/empty set mice display a shortened lifespan relative to TgCRND8+/empty set mice that are wild type for p73. Thus, p73 is required to protect the murine brain from tau hyperphosphorylation during aging and degeneration. (C) 2013 Elsevier Inc. All rights reserved.