Regorafenib modulates glucose metabolism, insulin/GLP-1 signaling, and tau pathology in an STZ-induced model of Alzheimer's disease.

Abstract

PURPOSE: Alzheimer's disease (AD), often described as "type 3 diabetes" due to its metabolic and neuroendocrine features, is marked by impaired glucose metabolism and insulin signaling. This study aimed to investigate whether regorafenib, a multi-kinase inhibitor, could modulate glucose metabolism, insulin/glucagon-like peptide-1 (GLP-1) pathways, and tau pathology in a streptozotocin (STZ)-induced rat model of AD. METHODS: Male rats (n = 5-8/group) received intracerebroventricular STZ to induce AD-like pathology and were subsequently treated with regorafenib for two weeks. Cognitive function was assessed using the Y-maze and novel object recognition (NOR) tests. Glucose metabolism was evaluated via 18F-FDG micro-PET imaging and glucose tolerance tests. Serum and hippocampal markers of insulin, GLP-1, and tau phosphorylation were measured. RESULTS: Regorafenib-treated rats exhibited significant improvement in recognition memory in the NOR test, while enhancement in spatial working memory in the Y-maze did not reach statistical significance. Regorafenib improved glucose metabolism in both the brain and periphery, as demonstrated by imaging and tolerance testing. Treatment significantly increased serum insulin and GLP-1 levels, and reduced hippocampal hyperphosphorylated tau, although hippocampal gene expression of insulin and GLP-1 signaling pathways remained unchanged. CONCLUSION: Regorafenib may provide neuroprotective benefits in AD by improving glucose metabolism and reducing tau pathology. These findings suggest regorafenib as a potential novel therapeutic strategy for AD, though further research is needed to confirm its efficacy, assess long-term outcomes, and elucidate underlying mechanisms.