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Role of p73 in Alzheimer disease: lack of association in mouse models or in human cohorts

Vardarajan, Badri; Vergote, David; Tissir, Fadel; Logue, Mark; Yang, Jing; Daude, Nathalie; Ando, Kunie; Rogaeva, Ekaterina; Lee, Joseph H.; Cheng, Rong; Brion, Jean-Pierre; Ghani, Mahdi; Shi, Beipei; Baldwin, Clinton; Kar, Satyabrata; Mayeux, Richard Paul; Fraser, Paul; Goffinet, André; George-Hyslop, Peter St; Farrer, Lindsay; Westaway, David

Background: P73 belongs to the p53 family of cell survival regulators with the corresponding locus Trp73 producing the N-terminally distinct isoforms, TAp73 and DeltaNp73. Recently, two studies have implicated the murine Trp73 in the modulation in phospho-tau accumulation in aged wild type mice and in young mice modeling Alzheimer’s disease (AD) suggesting that Trp73, particularly the DeltaNp73 isoform, links the accumulation of amyloid peptides to the creation of neurofibrillary tangles (NFTs). Here, we reevaluated tau pathologies in the same TgCRND8 mouse model as the previous studies. Results: Despite the use of the same animal models, our in vivo studies failed to demonstrate biochemical or histological evidence for misprocessing of tau in young compound Trp73+/- + TgCRND8 mice or in aged Trp73+/- mice analyzed at the ages reported previously, or older. Secondly, we analyzed an additional mouse model where the DeltaNp73 was specifically deleted and confirmed a lack of impact of the DeltaNp73 allele, either in heterozygous or homozygous form, upon tau pathology in aged mice. Lastly, we also examined human TP73 for single nucleotide polymorphisms (SNPs) and/or copy number variants in a meta-analysis of 10 AD genome-wide association datasets. No SNPs reached significance after correction for multiple testing and no duplications/deletions in TP73 were found in 549 cases of AD and 544 non-demented controls. Conclusion: Our results fail to support P73 as a contributor to AD pathogenesis.

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Also Published In

Title
Molecular Neurodegeneration
DOI
https://doi.org/10.1186/1750-1326-8-10

More About This Work

Academic Units
Epidemiology
Publisher
BioMed Central
Published Here
September 8, 2014

Notes

P73, Alzheimer’s disease, Animal models, GWAS

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