Generation of a humanized A beta 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; Marie Minh Thu Nguyen; Kelly Do Huynh; Javonillo, Dominic, I; Kristine Minh Tran; Phan, Jimmy; Jiang, Shan; Kramar, Eniko A.; Nunez-Diaz, Cristina; Balderrama-Gutierrez, Gabriela; Garcia, Franklin; Childs, Jessica; Rodriguez-Ortiz, Carlos J.; Antonio Garcia-Leon, Juan; 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.; LaFerla, Frank M.

VL / 12 - BP / - EP /
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 A beta under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse A beta 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 A beta sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hA beta 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 A beta under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.

Access level

Gold DOAJ, Green published