Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
David Baglietto‐Vargas, Stefânia Forner, Lena Cai, Alessandra Cadete Martini, Laura Trujillo‐Estrada, Vivek Swarup, Marie Minh Thu Nguyen, Kelly Do Huynh, Dominic I. Javonillo, Kristine M. Tran, Jimmy Phan, Shan Jiang, Enikö A. Kramár, Cristina Nuñez‐Diaz, Gabriela Balderrama-Gutierrez, Franklin Garcia, Jessica E. Childs, Carlos J. Rodríguez‐Ortiz, Juan Antonio García‐León, Masashi Kitazawa, Mohammad Shahnawaz, Dina P. Matheos, Xinyi Ma, Celia Da Cunha, Ken C. Walls, Rahasson R. Ager, Claudio Soto, Antonia Gutiérrez, Inés Moreno‐González, A Mortazavi, Andrea J. Tenner, Grant R. MacGregor, Marcelo A. Wood, Kim N. Green, Frank M. LaFerla
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.