title: Role of p73 in Alzheimer disease: lack of association in mouse models or in human cohorts.
abstract: 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.
  
  
  CONCLUSIONS
  Our results fail to support P73 as a contributor to AD pathogenesis.
authors: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors: Badri
authors: B
authors: Vardarajan
authors: David
authors: D
authors: Vergote
authors: Fadel
authors: F
authors: Tissir
authors: Mark
authors: M
authors: Logue
authors: Jing
authors: J
authors: Yang
authors: Nathalie
authors: N
authors: Daude
authors: Kunie
authors: K
authors: Ando
authors: Ekaterina
authors: E
authors: Rogaeva
authors: Joseph
authors: J
authors: Lee
authors: Rong
authors: R
authors: Cheng
authors: Jean-Pierre
authors: JP
authors: Brion
authors: Mahdi
authors: M
authors: Ghani
authors: Beipei
authors: B
authors: Shi
authors: Clinton T
authors: CT
authors: Baldwin
authors: Satyabrata
authors: S
authors: Kar
authors: Richard
authors: R
authors: Mayeux
authors: Paul
authors: P
authors: Fraser
authors: André M
authors: AM
authors: Goffinet
authors: Peter St
authors: PS
authors: George-Hyslop
authors: Lindsay A
authors: LA
authors: Farrer
authors: David
authors: D
authors: Westaway
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001572:Benzofurans; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D001572:Benzofurans; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011804:Quinolines; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D016875:tau Proteins