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

Mariana Pehar, Kenneth J. O'Riordan, Melissa Burns-Cusato, Matthew E. Andrzejewski, Carlos Gil del Alcazar, Corinna Burger, Heidi Scrable, Luigi Puglielli

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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 APP695/swe mice, a model of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)174-190
Number of pages17
JournalAging Cell
Volume9
Issue number2
DOIs
StatePublished - Apr 2010
Externally publishedYes

Fingerprint

Premature Mortality
Memory Disorders
Somatomedin Receptors
Haploinsufficiency
Microtubule Proteins
Amyloid beta-Protein Precursor
p53 Genes
Autophagy
Transgenes
Carrier Proteins
Alzheimer Disease
Protein Isoforms
Cell Death
Brain
Neoplasms

Keywords

  • Alzheimer's disease
  • Insulin-like growth factor 1 receptor
  • Memory loss
  • Neurodegeneration
  • p44
  • p53

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Pehar, M., O'Riordan, K. J., Burns-Cusato, M., Andrzejewski, M. E., del Alcazar, C. G., Burger, C., ... Puglielli, L. (2010). Altered longevity-assurance activity of p53: p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell, 9(2), 174-190. https://doi.org/10.1111/j.1474-9726.2010.00547.x

Altered longevity-assurance activity of p53 : p44 in the mouse causes memory loss, neurodegeneration and premature death. / Pehar, Mariana; O'Riordan, Kenneth J.; Burns-Cusato, Melissa; Andrzejewski, Matthew E.; del Alcazar, Carlos Gil; Burger, Corinna; Scrable, Heidi; Puglielli, Luigi.

In: Aging Cell, Vol. 9, No. 2, 04.2010, p. 174-190.

Research output: Contribution to journalArticle

Pehar, M, O'Riordan, KJ, Burns-Cusato, M, Andrzejewski, ME, del Alcazar, CG, Burger, C, Scrable, H & Puglielli, L 2010, 'Altered longevity-assurance activity of p53: p44 in the mouse causes memory loss, neurodegeneration and premature death', Aging Cell, vol. 9, no. 2, pp. 174-190. https://doi.org/10.1111/j.1474-9726.2010.00547.x
Pehar, Mariana ; O'Riordan, Kenneth J. ; Burns-Cusato, Melissa ; Andrzejewski, Matthew E. ; del Alcazar, Carlos Gil ; Burger, Corinna ; Scrable, Heidi ; Puglielli, Luigi. / Altered longevity-assurance activity of p53 : p44 in the mouse causes memory loss, neurodegeneration and premature death. In: Aging Cell. 2010 ; Vol. 9, No. 2. pp. 174-190.
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