| First Author | Sato K | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 3 | Pages | 101004 |
| PubMed ID | 34329683 | Mgi Jnum | J:312987 |
| Mgi Id | MGI:6792842 | Doi | 10.1016/j.jbc.2021.101004 |
| Citation | Sato K, et al. (2021) A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid beta peptide. J Biol Chem 297(3):101004 |
| abstractText | We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App(NL-G-F) and App(NL-F) mice, respectively). These models showed Abeta pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Abeta metabolism and clearance because the Arctic mutation renders Abeta resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Abeta antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Abeta by crossbreeding the App(NL-F) line with the Psen1(P117L/WT) line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than App(NL-G-F) mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD. |
