The Psen1‐L166P ‐knock‐in mutation leads to amyloid deposition in human wild‐type amyloid precursor protein YAC transgenic mice

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 ( A β PP ) or by knock‐in of the murine A β 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 β PP 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 A β PP nor overexpression of an A β PP 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 A β PP isoform using exogenous promoters.—Vidal, R., Sammeta, N., Garringer, H. J., Sambamurti, K., Miravalle, L., Lamb B. T., Ghetti, B. The Psen1‐L166P‐ knock‐in mutation leads to amyloid deposition in human wild‐type amyloid precursor protein YAC transgenic mice. FASEB J. 26, 2899–2910 (2012). www.fasebj.org