title: Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death.
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.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, WI 53705, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Riordan
authors.forename: Melissa
authors.initials: M
authors.lastname: Burns-Cusato
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Andrzejewski
authors.forename: Carlos Gil
authors.initials: CG
authors.lastname: del Alcazar
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
authors.forename: Heidi
authors.initials: H
authors.lastname: Scrable
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: 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
chemical_list: D010446:Peptide Fragments; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C503486:WDR77 protein, mouse; D016875:tau Proteins
references.citation: J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22
references.pmid: 15751225
references.citation: Neurobiol Aging. 2003 Jan-Feb;24(1):85-94
references.pmid: 12493554
references.citation: Nat Rev Neurosci. 2008 Oct;9(10):759-67
references.pmid: 18769445
references.citation: Neurobiol Aging. 2008 Jun;29(6):795-811
references.pmid: 17313996
references.citation: Clin Cancer Res. 2005 May 1;11(9):3155-62
references.pmid: 15867207
references.citation: Cancer Res. 1998 Feb 1;58(3):570-6
references.pmid: 9458107
references.citation: J Biol Chem. 2009 Jan 23;284(4):2482-92
references.pmid: 19011241
references.citation: Aging Cell. 2005 Apr;4(2):79-85
references.pmid: 15771611
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14376-81
references.pmid: 11121041
references.citation: Science. 2005 Jul 15;309(5733):476-81
references.pmid: 16020737
references.citation: BMB Rep. 2009 Jun 30;42(6):324-30
references.pmid: 19558789
references.citation: EMBO J. 2006 May 3;25(9):1997-2006
references.pmid: 16619032
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42
references.pmid: 18316725
references.citation: Curr Opin Neurol. 2005 Dec;18(6):740-7
references.pmid: 16280688
references.citation: Biochem J. 2007 Nov 1;407(3):383-95
references.pmid: 17425515
references.citation: Neuron. 1996 Nov;17(5):1005-13
references.pmid: 8938131
references.citation: Endocrine. 1997 Aug;7(1):119-24
references.pmid: 9449047
references.citation: Annu Rev Neurosci. 2001;24:1121-59
references.pmid: 11520930
references.citation: Nat Med. 2002 Dec;8(12):1390-7
references.pmid: 12415260
references.citation: Science. 1984 Sep 14;225(4667):1168-70
references.pmid: 6474172
references.citation: Mech Ageing Dev. 2009 Jan-Feb;130(1-2):10-7
references.pmid: 18639575
references.citation: Epilepsia. 2008 Sep;49(9):1562-9
references.pmid: 18503555
references.citation: Oncogene. 2002 Oct 3;21(44):6722-8
references.pmid: 12360399
references.citation: Mol Cell Biol. 2004 Sep;24(18):7987-97
references.pmid: 15340061
references.citation: Neurology. 2008 Nov 18;71(21):1702-8
references.pmid: 19015485
references.citation: FASEB J. 2009 Oct;23(10):3315-24
references.pmid: 19487308
references.citation: J Cell Sci. 2004 Mar 15;117(Pt 8):1525-32
references.pmid: 15020679
references.citation: Science. 2007 Jul 20;317(5836):369-72
references.pmid: 17641201
references.citation: Cell. 2005 Feb 25;120(4):449-60
references.pmid: 15734678
references.citation: Int J Clin Exp Pathol. 2008 Jan 01;1(2):157-68
references.pmid: 18784809
references.citation: Nature. 2003 Jan 9;421(6919):182-7
references.pmid: 12483226
references.citation: Genes Dev. 2004 Feb 1;18(3):306-19
references.pmid: 14871929
references.citation: Brain Dev. 2005 Jun;27(4):246-52
references.pmid: 15862185
references.citation: Nucleic Acids Res. 2007;35(22):7475-84
references.pmid: 17942417
references.citation: Pediatr Dev Pathol. 2007 May-Jun;10(3):208-23
references.pmid: 17535090
references.citation: Nature. 2006 Mar 16;440(7082):352-7
references.pmid: 16541076
references.citation: Nat Neurosci. 2005 Jan;8(1):79-84
references.pmid: 15608634
references.citation: Cell Death Differ. 2004 Oct;11(10):1066-75
references.pmid: 15195070
references.citation: Cell. 1993 Oct 8;75(1):59-72
references.pmid: 8402901
references.citation: Science. 2006 Sep 15;313(5793):1604-10
references.pmid: 16902091
references.citation: Nat Rev Mol Cell Biol. 2001 Aug;2(8):589-98
references.pmid: 11483992
references.citation: Am J Pathol. 2008 Sep;173(3):665-81
references.pmid: 18688038
references.citation: J Biol Chem. 2007 Aug 17;282(33):23818-28
references.pmid: 17548355
references.citation: Aging Cell. 2006 Oct;5(5):437-40
references.pmid: 16968311
references.citation: J Neurol Neurosurg Psychiatry. 2005 Jan;76(1):109-11
references.pmid: 15608007
references.citation: Cancer Res. 1998 Jun 1;58(11):2477-84
references.pmid: 9622092
references.citation: EMBO Rep. 2008 Sep;9(9):916-22
references.pmid: 18660751
references.citation: Nat Cell Biol. 2002 Jun;4(6):462-7
references.pmid: 12032546
references.citation: J Histochem Cytochem. 2008 Jun;56(6):615-27
references.pmid: 18379016
references.citation: Brain Res. 1989 Jan 16;477(1-2):90-9
references.pmid: 2495152
references.citation: Dev Biol. 2001 Jan 1;229(1):141-62
references.pmid: 11133160
references.citation: Biochem Pharmacol. 2008 Mar 1;75(5):1093-103
references.pmid: 18076866
references.citation: Trends Neurosci. 2001 Apr;24(4):219-24
references.pmid: 11250006
references.citation: Biochem J. 2005 Oct 1;391(Pt 1):59-67
references.pmid: 15966860
references.citation: Neurobiol Dis. 2003 Apr;12(3):194-211
references.pmid: 12742740
references.citation: Neurobiol Aging. 2005 Jun;26(6):929-37
references.pmid: 15718052
references.citation: Nat Rev Neurosci. 2007 Apr;8(4):287-99
references.pmid: 17375041
references.citation: Nature. 2002 Jan 3;415(6867):45-53
references.pmid: 11780111
references.citation: Acta Neuropathol. 2008 Jan;115(1):5-38
references.pmid: 18038275
references.citation: Genes Dev. 2005 Sep 15;19(18):2122-37
references.pmid: 16131611
references.citation: Brain Res Bull. 1982 Jun;8(6):771-4
references.pmid: 6182964
references.citation: Alzheimer Dis Assoc Disord. 1990 Winter;4(4):217-25
references.pmid: 2264979
references.citation: Dev Cell. 2002 Jan;2(1):9-19
references.pmid: 11782310
references.citation: Annu Rev Pathol. 2008;3:41-66
references.pmid: 18039130
references.citation: Trends Neurosci. 2006 Sep;29(9):528-35
references.pmid: 16859759