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

Abstract

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.

Loss of Cldn5 -and Increase in Irf7- In the Hippocampus and Cerebral Cortex of Diabetic Mice at the Early Symptomatic Stage

“…Numerous clinical studies have unveiled that individuals with long-term T2DM may exhibit mild cognitive impairments, especially in areas such as verbal memory, information processing speed, attention, and task execution [1,2]. In line with these observations, we have recently shown that adult mice with long-term T2DM display only minor learning impairments [3]. Acknowledging that the prolonged influence of T2DM could result in more profound cognitive deficits, and possibly even initiate the emergence of neurodegeneration [1,4,5], we have here analysed the pattern of gene expression of the cortex and hippocampus of these adult, chronically T2DM, mice.…”

“…In a recent publication we showed that wild type mice subjected to the HFD and STZ experimental setup develop classical signs of metabolic syndrome, including weight gain, hyperglycaemia and impaired response to the glucose and insulin tolerance tests [3]. In the same work, subjecting these mice to various cognitive assessments, including the Y maze, open field, novel object recognition, and Barnes maze, revealed -minordeficits in the Barnes and the Y maze [3].…”

“…In a recent publication we showed that wild type mice subjected to the HFD and STZ experimental setup develop classical signs of metabolic syndrome, including weight gain, hyperglycaemia and impaired response to the glucose and insulin tolerance tests [3]. In the same work, subjecting these mice to various cognitive assessments, including the Y maze, open field, novel object recognition, and Barnes maze, revealed -minordeficits in the Barnes and the Y maze [3]. To gain mechanistic insights on how T2DM might be leading to these brain function changes, we carried out a transcriptomic analysis of cortical and hippocampal samples from control and the same T2DM mice used for the behavioral studies.…”

“…Mice between 7 and 9 months of age were subjected to HFD for 14 weeks, at which time an intraperitoneal injection of STZ (40mg/kg) per day was performed for 5 days [3,6]. Although STZ is a compound commonly used as an experimental model of type 1 diabetes (since this antibiotic induces the destruction of pancreatic ß cells leading to hypoinsulinemia and hyperglucemia), its use at multiple low doses and in combination with HFD allows it to mimic the final stages of T2DM [6].…”

“…After the STZ treatment, HFD was continued for another 6 weeks (age of the mice at the end of the experiment was 12-14 months). Behavioral tests, immunoblotting, antibodies, RNA-sequencing and data analysis, transcript enrichment analysis and statistical analysis have been described in the previous publication [3] and are also summarized in the legends of figures and as supplementary information.…”