Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology

David Baglietto‐Vargas(University of California, Irvine), Stefânia Forner(University of California, Irvine), Lena Cai(University of California, Irvine), Alessandra Cadete Martini(University of California, Irvine), Laura Trujillo‐Estrada(University of California, Irvine), Vivek Swarup(University of California, Irvine), Marie Minh Thu Nguyen(University of California, Irvine), Kelly Do Huynh(University of California, Irvine), Dominic I. Javonillo(University of California, Irvine), Kristine M. Tran(University of California, Irvine), Jimmy Phan(University of California, Irvine), Shan Jiang(University of California, Irvine), Enikö A. Kramár(University of California, Irvine), Cristina Nuñez‐Diaz(Biomedical Research Networking Center on Neurodegenerative Diseases), Gabriela Balderrama-Gutierrez(University of California, Irvine), Franklin Garcia(University of California, Irvine), Jessica E. Childs(University of California, Irvine), Carlos J. Rodríguez‐Ortiz(University of California, Irvine), Juan Antonio García‐León(Biomedical Research Networking Center on Neurodegenerative Diseases), Masashi Kitazawa(University of California, Irvine), Mohammad Shahnawaz(The University of Texas Health Science Center at Houston), Dina P. Matheos(University of California, Irvine), Xinyi Ma(University of California, Irvine), Celia Da Cunha(University of California, Irvine), Ken C. Walls(University of California, Irvine), Rahasson R. Ager(University of California, Irvine), Claudio Soto(The University of Texas Health Science Center at Houston), Antonia Gutiérrez(Biomedical Research Networking Center on Neurodegenerative Diseases), Inés Moreno‐González(Biomedical Research Networking Center on Neurodegenerative Diseases), A Mortazavi(University of California, Irvine), Andrea J. Tenner(University of California, Irvine), Grant R. MacGregor(University of California, Irvine), Marcelo A. Wood(University of California, Irvine), Kim N. Green(University of California, Irvine), Frank M. LaFerla(University of California, Irvine)
Nature Communications
April 23, 2021
10.1038/s41467-021-22624-z
Cited by 114Open Access
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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.

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