학술논문
Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.
Document Type
article
Author
Baglietto-Vargas, David; Forner, Stefania; Cai, Lena; Martini, Alessandra C; Trujillo-Estrada, Laura; Swarup, Vivek; Nguyen, Marie Minh Thu; Do Huynh, Kelly; Javonillo, Dominic I; Tran, Kristine Minh; Phan, Jimmy; Jiang, Shan; Kramár, Enikö A; Nuñez-Diaz, Cristina; Balderrama-Gutierrez, Gabriela; Garcia, Franklin; Childs, Jessica; Rodriguez-Ortiz, Carlos J; Garcia-Leon, Juan Antonio; Kitazawa, Masashi; Shahnawaz, Mohammad; Matheos, Dina P; Ma, Xinyi; Da Cunha, Celia; Walls, Ken C; Ager, Rahasson R; Soto, Claudio; Gutierrez, Antonia; Moreno-Gonzalez, Ines; Mortazavi, Ali; Tenner, Andrea J; MacGregor, Grant R; Wood, Marcelo; Green, Kim N; LaFerla, Frank M
Source
Nature communications. 12(1)
Subject
Language
Abstract
The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.