S1‐02‐02: p73 regulates neurodegeneration, stem cell self‐renewal, and phospho‐Tau accumulation during aging and Alzheimer's disease

The genetic mechanisms that regulate neurodegeneration are only poorly-understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Haploinsufficiency for p73 occurs in the human population. A combination of genetic and molecular methods, including analysis of p73, ΔNp73, and TAp73 knockout mice and in utero electroporation of RNAi into embryonic stem cells were used to determine the role of p73 in the nervous system. Behavioral analyses demonstrated that old, but not young, p73+/− mice displayed reduced motor and cognitive function, CNS atrophy and neuronal degeneration. Unexpectedly, brains of aged p73+/− mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mutant amyloid precursor protein mouse model of AD, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/− neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. We found a second important role for p73 in the nervous system. p73 exists as transactivating (TA) and transactivation domain-deleted (ΔN) isoforms. Examination of ΔNp73-/- mice showed that it is required for neuronal survival, while TAp73-/- mice exhibit hippocampal dysgenesis, which involves a selective loss of the lower blade of the dentate gyrus. In adult TAp73-/- mice, the hippocampal precursors that are responsible for ongoing neurogenesis are significantly depleted, and neurogenesis is greatly decreased resulting in the dysgenesis. Genetic knockdown of TAp73 in embryonic cortical precursors led to decreased precursor proliferation and increased neuronal differentiation, both in culture and in vivo. This decreased embryonic self-renewal ultimately resulted in a smaller pool of neural stem cells in the adult SVZ. These data indicate that p73 has two roles: it is essential for (1) for preventing neurodegeneration and phospho-tau accumulation, and (2) promoting the self-renewal of neural stem cells. We suggest that p73 maintains the adult nervous system, and may be a susceptibility factor for AD and other neurodegenerative disorders.