Amyloid pathology and cognitive impairment in hAβ-KI and APPSAA-KI mouse models of Alzheimer's disease

The hAβ-KI and APP^SAA-KI are two amyloid models that harbor mutations in the endogenous mouse App gene. Both hAβ-KI and APP^SAA-KI mice contain a humanized Aβ sequence, and APP^SAA-KI mice carry three additional familial AD mutations. We herein report that the Aβ levels and Aβ42/Aβ40 ratio in APP^SAA-KI homozygotes are dramatically higher than those in hAβ-KI homozygotes at 14 months of age. In addition, APP^SAA-KI mice display a widespread distribution of amyloid plaques in the brain, whereas the plaques are undetectable in hAβ-KI mice. Moreover, there are no sex differences in amyloid pathology in APP^SAA-KI mice. Both APP^SAA-KI and hAβ-KI mice exhibit cognitive impairments, wherein no significant differences are found between these two models, although APP^SAA KI mice show a trend towards worse cognitive function. Notably, female hAβ-KI and APP^SAA-KI mice have a more pronounced cognitive impairments compared to their respective males. Our findings suggest that Aβ humanization contributes to cognitive deficits in APP^SAA-KI mice, and that amyloid deposition might not be closely associated with cognitive impairments in APP^SAA-KI mice.