학술논문
Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
Document Type
Original Paper
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
English
ISSN
2041-1723
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.
Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.
Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.