Tirzepatide prevents neurodegeneration through multiple molecular pathways: An emerging therapeutic strategy for the treatment of cognitive impairment

Background: Insulin resistance in type 2 diabetes (T2DM) patients can lead to -amyloid accumulation and tau hyperphosphorylation, which are the hallmark of Alzheimer’s Disease (AD)-associated neurodegeneration. This, combined with other pathophysiological aspects shared by T2DM and AD, has paved the way for further investigation into the therapeutic effects of antidiabetic medications on dementia treatment. Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce the risk of dementia in T2DM patients by improving memory, learning, and overcoming cognitive impairment. While GLP-1 RAs have been effective in improving glycemic control, dual (Gastric inhibitory polypeptide) GIP/GLP-1 RAs, like Tirzepatide (TIR), have shown even greater efficacy in reducing blood glucose levels and HbA1c, providing better overall glycemic management for patients with T2DM. Thus, the combination of GIP and GLP-1 receptor activation may provide synergistic effects in providing enhanced neuroprotective effects. A protective effect of TIR, against learning and memory impairment has also been demonstrated in diabetic mice but the molecular processes involved are still unknown. Methods: In this study, we investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration for 7 days. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miR-34a), apoptosis (miR-212), and differentiation (miR-29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through FACS. mRNA and miRNA expression were examined by RT-PCR and protein levels by Western Blot. The methylation profile of the studied genes were evaluated by Pyrosequencing. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures. Results: For the first time, it was highlighted: a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; b) TIR efficacy in neuroprotection; c) TIR counteracting of hyperglycemia and insulin resistance-related effects and (d) The data on CREB and BDNF promoter methylation and in miR-34a, miR-212, and miR-29c levels, evidenced the overcoming TIR effects hyperglycemia induced-epigenetic modifications. Conclusions: We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Further, TIR also modulates the epigenetic alteration, thereby alleviating the detrimental effects of elevated glucose levels on neurons. Thus, this study provides new insight into the potential role of TIR in improvement and comprehensive management of diabetes related neuropathy.