title: Modeling Alzheimer's disease in mouse without mutant protein overexpression: cooperative and independent effects of Aβ and tau.
abstract: BACKGROUND
  Alzheimer's disease (AD), the most common cause of dementia in the elderly, has two pathological hallmarks: Aβ plaques and aggregation of hyperphosphorylated tau (p-tau). Aβ is a cleavage product of Amyloid Precursor Protein (APP). Presenilin 1 (PS1) and presenilin 2 (PS2) are the catalytic subunit of γ-secretase, which cleaves APP and mediates Aβ production. Genetic mutations in APP, PSEN1 or PSEN2 can lead to early onset of familial AD (FAD). Although mutations in the tau encoding gene MAPT leads to a subtype of frontotemporal dementia and these mutations have been used to model AD tauopathy, no MAPT mutations have been found to be associated with AD.
  
  
  RESULTS
  To model AD pathophysiology in mice without the gross overexpression of mutant transgenes, we created a humanized AD mouse model by crossing the APP and PSEN1 FAD knock-in mice with the htau mice which express wildtype human MAPT genomic DNA on mouse MAPT null background (APP/PS1/htau). The APP/PS1/htau mice displayed mild, age-dependent, Aβ plaques and tau hyperphosphorylation, thus successfully recapitulating the late-onset AD pathological hallmarks. Selected biochemical analyses, including p-tau western blot, γ-secretase activity assay, and Aβ ELISA, were performed to study the interaction between Aβ and p-tau. Subsequent behavioral studies revealed that the APP/PS1/htau mice showed reduced mobility in old ages and exaggerated fear response. Genetic analysis suggested that the fear phenotype is due to a synergic interaction between Aβ and p-tau, and it can be completely abolished by tau deletion.
  
  
  CONCLUSIONS
  The APP/PS1/htau model represents a valuable and disease-relevant late-onset pre-clinical AD animal model because it incorporates human AD genetics without mutant protein overexpression. Analysis of the mice revealed both cooperative and independent effects of Aβ and p-tau.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Guo
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Allysa L
authors.initials: AL
authors.lastname: Cole
authors.forename: Ji-Yeun
authors.initials: JY
authors.lastname: Hur
authors.forename: Yueming
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D005239:Fear; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D006801:Humans; D018782:Maze Learning; D008568:Memory; D051379:Mice; D009068:Movement; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053763:Presenilins / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D050505:Mutant Proteins; D053763:Presenilins; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases