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 ?-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-? precursor protein (A?PP) or by knock-in of the murine A?pp 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 A?PP and the L166P presenilin 1 mutation. At ?6 mo of age, double-mutant mice develop amyloid pathology, with signs of neuritic dystrophy, intracellular A? accumulation, and glial inflammation, an increase in A?PP C-terminal fragments, and an 8 times increase in A?42 levels with a 40% decrease in A?40 levels, leading to a significant increase (14 times) of A?42/A?40 ratios, with minimal effects on presenilin or the Notch1 pathway in the brain. We conclude that in mice, neither mutations in A?PP nor overexpression of an A?PP isoform are a prerequisite for A? 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 A?PP isoform using exogenous promoters.

SUBMITTER: Vidal R 

PROVIDER: S-EPMC3382098 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature