RNAseq of the cerebral cortex of wild type mices and human amyloid peptide-expressing mice ( NL/F) affected by T2DM, both with normal metabolic state.. RNAseq analysis of the cortex of wild type and human amyloid peptide-expressing mice (NL/F)

In this work we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in late middle-aged hAPP NL/F mice, a knockin strain with high levels of Aβ42 peptide but with no significant cognitive alterations. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared to wild type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. Bioinformatic analysis of the RNAseq of the cerebral cortex of hAPP NL/F and wild type mice suggests that the former could be more susceptible to T2DM due to defects in plasma membrane permeability. This works indicates that chronic T2DM is not sufficient in itself to lead to severe cognitive disorders, but it makes them emerge in a predisposed background.