Loss of Cldn5 -and increase in Irf7-in the hippocampus and cerebral cortex of diabetic mice at the early symptomatic stage.

Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor ß-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM.

Cognitive decline in diabetic mice predisposed to Alzheimer's disease is greater than in wild type.

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 middle-aged hAPP NL/F mice, a preclinical model of Alzheimer's disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aß or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.