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- Title
Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.
- Authors
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
- 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.
- Subjects
TRANSGENIC mice; MICE; ALZHEIMER'S disease; NEUROPLASTICITY; MOUSE diseases; PATHOLOGY
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22624-z