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The effects of pathogenic mutations in the APP and PSEN1 genes on in vivo G‐secretase activity are additive
Author(s) -
Sato Kaori,
Nagata Kenichi,
Saido Takaomi C.,
Sasaguri Hiroki
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042378
Subject(s) - psen1 , in vivo , mutation , gene knockin , gene , biology , phenotype , microbiology and biotechnology , presenilin , genetics , medicine , pathology , alzheimer's disease , disease
Background Pathogenic mutations associated with early‐onset familial AD have been identified in the APP and PSEN genes, all of which are primarily involved in the processing of Aβ production. However, the combinatorial effects of mutations in both the genes against AD pathology in vivo remain unresolved. Method We generated double knock‐in mice harboring Swedish/Iberian and P117L mutations in the endogenous App and Psen1 genes, respectively, carrying a humanized Aβ sequence. We performed biological and histochemical analysis to explore additional Psen1 mutation alter the App mutations‐derived Aβ pathology or APP processing by β and γ‐secretase. Result The double knock‐in mice showed a drastic increase in Aβ 42 secretion more than 20‐fold compared to that of single App knock‐in mice. It is also noteworthy that Aβ plaque formation can be detected in the brains of double knock‐in mice as young as 3 months of age. Conclusion Our results indicate that the effects derived from the App and Psen1 mutations are additive and strongly accelerate production of insoluble Aβ42 prone to aggregate, and then form detectable plaques without any mutation inside the Aβ sequence at ages younger than the single App NL‐F knock‐in mice.