No more brain tangles with DeltaNp73

Abstract

In Alzheimer's disease (AD), neurons suffer dysfunction and death associated with aberrant tau phosphorylation and subsequent neurofibrillary tangles. A new study reveals a surprising neuroprotective role for a truncated p73 isoform (DeltaNp73). Aged mice with reduced DeltaNp73 levels exhibit tau pathology and cognitive deficits, and DeltaNp73 reduction in mice with amyloid pathology causes extensive tangle formation and neuron death. These findings provide a novel animal model of AD and a potential therapeutic role for DeltaNp73 inducers.

Figure 1

Possible pathways by which ΔNp73 modifies brain aging and the pathogenesis of Alzheimer's disease. By acting as a negative regulator of p53 and by directly inhibiting JNK ΔNp73 protects neurons against degeneration. A. Overexpression of p53 as well as deletion of one allele of Tp63 or one allele of ΔNp73 causes accelerated aging and neurodegeneration. B. Downstream targets of ΔNp73. ΔNp73 inhibits p53 activity and this reduces the levels of Bax, p21 and Apaf-1. ΔNp73 interacts with JNK and inhibits its activity resulting in reduced tau phosphorylation, decreased neuronal vulnerability and preserved synaptic plasticity. As p53 levels are not changed in Tp73+/− mice, the major pathway is probably via JNK. Reduced levels of ΔNp73 in the Tp73+/− mice or in AD removes the inhibition of ΔNp73 on JNK and p53 activities thereby triggering neuronal death. These pathways can partially explain how ΔNp73 might preserve cognitive ability during aging and in AD.