Knock-in rats with homozygous PSEN1 Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43.

Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of β-amyloid (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from amyloid precursor protein fragments. Psen1 KO mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1 ) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of Alzheimer's disease-causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regard to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1 mutation. In this study, we focused on young Psen1 rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1 mice, Psen1 rats survive into adulthood despite loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1 rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in Psen1 and Psen1 rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 Alzheimer's disease-associated mutations on neurodegeneration in older animals.

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