Amyloid pathology and cognitive impairment in hAβ-KI and APP(SAA)-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.