Diabetes-associated cognitive decline in mice with genetic predisposition to Alzheimer's disease, not in wild type

A significant number of individuals with type 2 diabetes (T2DM) develop cognitive deficits over time that in some cases could lead to dementia. It remains to be identified the diabetes-related factors or comorbid conditions that drive the association and how they work. In this manuscript, we show that 14-15 month-old hAPP NL/F mice, a knock‐in mouse model of preclinical Alzheimer’s disease (AD) (that is, they generate Aβ42 at an early age but do not show symptoms of the disease until they are old), but not wild type, develop behavioural deficits that correlate with electrophysiological and dendritic spine changes when affected by T2DM. The deficits are not paralleled by higher levels of toxic forms of amyloid beta-peptide (Aβ ) or by neuroinflammation but by a reduction in γ -secretase activity, in turn accountable, among other consequences, for a reduction in the levels of the synaptogenesis regulator protein PSD95, and by increased phosphorylation of Tau at epitopes of dendritic spine targeting. RNAseq analysis of the cerebral cortex of wild type and hAPP NL/F, with and without T2DM, revealed the significant downregulation of hypoxia inducible factor 3 (HIF-3α) in the hAPP NL/F diabetic mice only, a decrease that was also observed at the protein level. The main conclusion of this work is that T2DM will trigger or accelerate cognitive illness fundamentally in those individuals who already have a genetic predisposition to AD. A second conclusion is that the cognitive disorders produced by diabetes in these individuals are not due to the excess of toxic forms of Aβ but to other causes, including loss of function of γ -secretase. The third conclusion is that an alteration of the response to hypoxia through Hif3α would be mediating the negative effects of T2DM in the brain.