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

Abstract

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-months 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.

Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin‐4 treatment

“…Recently, Ex4 was shown to restore spatial memory and reduce ADlike histopathology in APP/PS1 mice (Bomfim et al, 2012) and APP mice (Robinson et al, 2019). In our study, the mechanism of action of Ex4 against the AD-like features (tau, neuronal loss, Aβ, learning impairment) was not directly related to effect on the insulin signaling pathway (no modulation of insulin signaling pathway protein levels or phosphorylation, data not shown).…”

“…Although, this was not the case in Tg2576 AD mice. While Ex4 treatment for 8 months did not significantly impact serum insulin levels, when Ex4 was combined with intranasal insulin, there was no additive or synergistic effect on Aβ levels and learning functions in Tg2576 mice (Robinson et al, 2019).…”

“…These results are supported by the demonstration that Ex4 increased neurogenesis in Parkinson disease mouse model (Bertilsson et al., 2008) and increased synaptic plasticity and long‐term potentiation in normal brain slices exposed to Aβ (Gault & Holscher, 2008). Recently, Ex4 was shown to restore spatial memory and reduce AD‐like histopathology in APP/PS1 mice (Bomfim et al., 2012) and APP mice (Robinson et al., 2019). In our study, the mechanism of action of Ex4 against the AD‐like features (tau, neuronal loss, Aβ, learning impairment) was not directly related to effect on the insulin signaling pathway (no modulation of insulin signaling pathway protein levels or phosphorylation, data not shown).…”

“…Although, this was not the case in Tg2576 AD mice. While Ex4 treatment for 8 months did not significantly impact serum insulin levels, when Ex4 was combined with intranasal insulin, there was no additive or synergistic effect on Aβ levels and learning functions in Tg2576 mice (Robinson et al., 2019). In addition to the increased plasma insulin levels, as also observed in 3xTg AD mice (Li et al., 2010), Ex4 treatment significantly reversed diabetes‐induced changes in adiponectin and triglycerides levels, supporting their inversed relationship (Christou & Kiortsis, 2013).…”

Alleviation of Depression by Glucagon-Like Peptide 1 Through the Regulation of Neuroinflammation, Neurotransmitters, Neurogenesis, and Synaptic Function

“…A recent study demonstrated that GLP-1 has a neurotrophic effect and promotes neurotrophic processes in the brain (Mainardi et al, 2015). Robinson et al demonstrated that a mixture of GLP-1 agonists boosts memory and improves insulin action in the brain (Robinson et al, 2019). Exendin-4, a stable synthetic form of GLP-1, is commonly used clinically for diabetes treatment because GLP-1 has a short half-life (Drucker and Nauck, 2006;Heppner et al, 2015b).…”