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

  • Author(s): 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;
  • LaFerla, Frank M
  • et al.
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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