p73 haploinsufficiency causes tau hyperphosphorylation and tau kinase dysregulation in mouse models of aging and Alzheimer's disease |
| |
Authors: | Gonzalo I. Cancino Freda D. Miller David R. Kaplan |
| |
Affiliation: | 1. Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada;2. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada;3. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada |
| |
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 GSK3β, 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+?Ø 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 GSK3β, c-Abl, and Cdk5 in the brains of both of these mouse models. Moreover, p73+?−;TgCRND8+?Ø mice display a shortened lifespan relative to TgCRND8+?Ø mice that are wild type for p73. Thus, p73 is required to protect the murine brain from tau hyperphosphorylation during aging and degeneration. |
| |
Keywords: | p73 p53 family Tau phosphorylation Pin1 Alzheimer's disease Aging Neurodegeneration GSK-3β c-Abl Cdk5 Tauopathy Paired helical filaments TgCRND8 |
本文献已被 ScienceDirect 等数据库收录! |
|