Generation of a humanized A? expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology

Abstract The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models the harbor pathogenic mutations, rendering them better representations familial autosomal-dominant forms disease. Here, we generated knock-in mice that express wildtype human A? under control App locus. Remarkably, changing 3 amino acids in sequence to its wild-type counterpart leads age-dependent impairments cognition synaptic plasticity, brain volumetric changes, inflammatory alterations, appearance Periodic Acid-Schiff (PAS) granules changes gene expression. In addition, when exon 14 encoding was flanked by loxP sites show Cre-mediated excision ablates hA? expression, rescues reduces formation PAS granules.