Abstract
BackgroundP73 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.ResultsDespite 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.ConclusionOur results fail to support P73 as a contributor to AD pathogenesis.
Highlights
P73 belongs to the p53 family of cell survival regulators with the corresponding locus Trp73 producing the N-terminally distinct isoforms, TAp73 and DeltaNp73
The finding that mice haploinsufficient for the murine Trp73 locus, a member of the Trp53 gene family enriched in the nervous system, are prone to develop tau pathology in presence of an APP transgene [19] attracted a degree of attention [20]
Because other studies found borderline evidence for an association between genetic or copy number variants in the human p73 gene (TP73) and risk for Alzheimer’s disease (AD) [23,24], we evaluated the possible association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in the human TP73 gene with AD in several large datasets
Summary
P73 belongs to the p53 family of cell survival regulators with the corresponding locus Trp producing the N-terminally distinct isoforms, TAp73 and DeltaNp73. Besides “3R” and “4R” tau mRNA splicing variants (encoding different numbers of microtubule binding domains) under developmental and neuroanatomical control ([18] and references therein), one possibility for the failure of wt mouse tau to form NFTs is a distinction between mice and humans within a chemical pathway that acts to link Aβ accumulation to tau In this context, the finding that mice haploinsufficient for the murine Trp locus, a member of the Trp gene family enriched in the nervous system, are prone to develop tau pathology in presence of an APP transgene [19] attracted a degree of attention [20]. The results presented here fail to define a genetic association between the p73 locus and AD pathology in mouse models and in human cohorts
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