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

Baglietto-Vargas, David; Forner, Stefania; Cai, Lena; Martini, Alessandra C.; Trujillo-Estrada, Laura; Swarup, Vivek; Nguyen, Marie Minh Thu; 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; 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.

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

David Baglietto-Vargas, Stefania Forner, Lena Cai, Alessandra C. Martini, Laura Trujillo-Estrada, Vivek Swarup, Marie Minh Thu Nguyen, Kelly Huynh, Dominic I. Javonillo, Kristine Minh Tran, Jimmy Phan, Shan Jiang, Enikö A. Kramár, Cristina Nuñez-Diaz, Gabriela Balderrama-Gutierrez, Franklin Garcia, Jessica Childs, Carlos J. Rodriguez-Ortiz, Juan Antonio Garcia-Leon, Masashi Kitazawa, Mohammad Shahnawaz, Dina P. Matheos, Xinyi Ma, Celia Cunha, Ken C. Walls, Rahasson R. Ager, Claudio Soto, Antonia Gutierrez, Ines Moreno-Gonzalez, Ali Mortazavi, Andrea J. Tenner, Grant R. MacGregor, Marcelo Wood, Kim N. Green () and Frank M. LaFerla ()
Additional contact information
David Baglietto-Vargas: University of California
Stefania Forner: University of California
Lena Cai: University of California
Alessandra C. Martini: University of California
Laura Trujillo-Estrada: University of California
Vivek Swarup: University of California
Marie Minh Thu Nguyen: University of California
Kelly Huynh: University of California
Dominic I. Javonillo: University of California
Kristine Minh Tran: University of California
Jimmy Phan: University of California
Shan Jiang: University of California
Enikö A. Kramár: University of California
Cristina Nuñez-Diaz: Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga
Gabriela Balderrama-Gutierrez: University of California
Franklin Garcia: University of California
Jessica Childs: University of California
Carlos J. Rodriguez-Ortiz: University of California
Juan Antonio Garcia-Leon: Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga
Masashi Kitazawa: University of California
Mohammad Shahnawaz: University of Texas Health Science Center at Houston
Dina P. Matheos: University of California
Xinyi Ma: University of California
Celia Cunha: University of California
Ken C. Walls: University of California
Rahasson R. Ager: University of California
Claudio Soto: University of Texas Health Science Center at Houston
Antonia Gutierrez: Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga
Ines Moreno-Gonzalez: Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga
Ali Mortazavi: University of California
Andrea J. Tenner: University of California
Grant R. MacGregor: University of California
Marcelo Wood: University of California
Kim N. Green: University of California
Frank M. LaFerla: University of California

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22624-z

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