Altered Longevity-assurance Activity of P53:p44 in the Mouse Causes Memory Loss, Neurodegeneration and Premature Death

Overview

Journal Aging Cell

Specialties Cell Biology
Geriatrics

Date 2010 Apr 23

PMID 20409077

Citations 57

Authors

Mariana Pehar

Kenneth J ORiordan

Melissa Burns-Cusato

Matthew E Andrzejewski

Carlos Gil Del Alcazar

Corinna Burger

Heidi Scrable

Luigi Puglielli

Affiliations

Soon will be listed here.

Abstract

The longevity-assurance activity of the tumor suppressor p53 depends on the levels of Delta40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44(+/+)) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a 'humanized' form of the amyloid precursor protein (APP), p44(+/+) animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP(695/swe) mice, a model of Alzheimer's disease.

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