| First Author | Vidal R | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 7 | Pages | 2899-910 |
| PubMed ID | 22459153 | Mgi Jnum | J:187475 |
| Mgi Id | MGI:5437177 | Doi | 10.1096/fj.12-205542 |
| Citation | Vidal R, et al. (2012) The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice. FASEB J 26(7):2899-910 |
| abstractText | Genetically engineered mice have been generated to model cerebral beta-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-beta precursor protein (AbetaPP) or by knock-in of the murine Abetapp 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 AbetaPP and the L166P presenilin 1 mutation. At approximately 6 mo of age, double-mutant mice develop amyloid pathology, with signs of neuritic dystrophy, intracellular Abeta accumulation, and glial inflammation, an increase in AbetaPP C-terminal fragments, and an 8 times increase in Abeta42 levels with a 40% decrease in Abeta40 levels, leading to a significant increase (14 times) of Abeta42/Abeta40 ratios, with minimal effects on presenilin or the Notch1 pathway in the brain. We conclude that in mice, neither mutations in AbetaPP nor overexpression of an AbetaPP isoform are a prerequisite for Abeta 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 AbetaPP isoform using exogenous promoters. |
