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

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.

Automated summary

The researchers created a mouse model that expresses wildtype human A β, demonstrating effects on cognition, synaptic plasticity, brain changes, inflammation, PAS granules, and gene expression. Furthermore, excision of exon 14 through Cre-mediated methods reduced A β expression and rescued cognitive impairments.