Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer’s Disease
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Disruption of brain insulin signaling may explain the higher Alzheimer’s disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15–30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.
KeywordsInsulin Exenatide Alzheimer’s disease T2D
The research conducted was supported by NIH grants R01 AG034087, R01 AG051545 for Dr. Beeri, VA Merit grant 1I01BX002267 for Dr. Haroutunian, as well as the Leroy Schecter Foundation and the Bader Philanthropies for Dr. Beeri.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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