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

Nat Commun. 2021 Apr 23;12(1):2421. doi: 10.1038/s41467-021-22624-z.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Brain / metabolism
  • Brain / physiopathology*
  • Disease Models, Animal*
  • Female
  • Gene Expression Profiling / methods
  • Gene Ontology
  • Gene Regulatory Networks
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation*
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor