1. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.
- Author
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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, and LaFerla, Frank M
- Subjects
Brain ,Animals ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Humans ,Alzheimer Disease ,Disease Models ,Animal ,Amyloid beta-Protein Precursor ,Gene Expression Profiling ,Neuronal Plasticity ,Mutation ,Female ,Male ,Gene Regulatory Networks ,Amyloid beta-Peptides ,Gene Ontology ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Dementia ,Acquired Cognitive Impairment ,Neurosciences ,Genetics ,Alzheimer's Disease ,Brain Disorders ,2.1 Biological and endogenous factors ,Neurological - 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.
- Published
- 2021