Open AccessAltered longevity‐assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death
Author(s) -
Pehar Mariana,
O’Riordan Kenneth J.,
BurnsCusato Melissa,
Andrzejewski Matthew E.,
Del Alcazar Carlos Gil,
Burger Corinna,
Scrable Heidi,
Puglielli Luigi
Publication year - 2010
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2010.00547.x
Subject(s) - neurodegeneration , haploinsufficiency , biology , neuroscience , genetically modified mouse , transgene , cognitive decline , microbiology and biotechnology , medicine , genetics , disease , gene , dementia , phenotype
Summary The longevity‐assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (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.