title: The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice.
abstract: Genetically engineered mice have been generated to model cerebral β-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-β precursor protein (AβPP) or by knock-in of the murine Aβpp gene alone or with presenilin1 mutations. Here we describe the generation and initial characterization of a new mouse line based on the presence of 2 copies of the human genomic region encoding the wild-type AβPP and the L166P presenilin 1 mutation. At ∼6 mo of age, double-mutant mice develop amyloid pathology, with signs of neuritic dystrophy, intracellular Aβ accumulation, and glial inflammation, an increase in AβPP C-terminal fragments, and an 8 times increase in Aβ42 levels with a 40% decrease in Aβ40 levels, leading to a significant increase (14 times) of Aβ42/Aβ40 ratios, with minimal effects on presenilin or the Notch1 pathway in the brain. We conclude that in mice, neither mutations in AβPP nor overexpression of an AβPP isoform are a prerequisite for Aβ pathology. This model will allow the study of AD pathogenesis and testing of therapeutic strategies in a more relevant environment without experimental artifacts due to the overexpression of a single-mutant AβPP isoform using exogenous promoters.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. rvidal@iupui.edu
authors.forename: Ruben
authors.initials: R
authors.lastname: Vidal
authors.forename: Neeraja
authors.initials: N
authors.lastname: Sammeta
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Garringer
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Leticia
authors.initials: L
authors.lastname: Miravalle
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D018076:DNA, Complementary; D050505:Mutant Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch; D011994:Recombinant Proteins