Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death.
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.
Pehar
Mariana
M
Department of Medicine, University of Wisconsin-Madison, WI 53705, USA.
O'Riordan
Kenneth J
KJ
Burns-Cusato
Melissa
M
Andrzejewski
Matthew E
ME
del Alcazar
Carlos Gil
CG
Burger
Corinna
C
Scrable
Heidi
H
Puglielli
Luigi
L
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D008136:Longevity; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000172:deficiency / Q000378:metabolism
D010446:Peptide Fragments; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C503486:WDR77 protein, mouse; D016875:tau Proteins
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