Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death

Aging Cell. 2010 Apr;9(2):174-90. doi: 10.1111/j.1474-9726.2010.00547.x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy
  • Longevity*
  • Memory Disorders / genetics
  • Memory Disorders / metabolism*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Signal Transduction
  • Transcription Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • tau Proteins / deficiency
  • tau Proteins / metabolism


  • Peptide Fragments
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • WDR77 protein, mouse
  • tau Proteins