The role of IGF1 signaling in remote ischemic conditioning-mediated amelioration of Alzheimer's disease pathology and cerebral insulin resistance.

BACKGROUND: Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) share common pathological features, notably insulin resistance. Remote ischemic conditioning (RIC) is a clinically validated intervention with broad distant organ protection. Nevertheless, RIC's effects on cerebral insulin resistance (CIR) in AD animal models remain poorly understood. This study aims to investigate RIC's effects in reducing CIR and AD pathology across models. METHODS: The study used ICV streptozotocin (STZ) to induce sporadic AD (sAD) and APP/PS1 transgenic rats as familial AD (fAD) models. RIC was established by three cycles of five minutes of ischemia followd by five minutes of reperfusion in rats' hindlimbs, conducted five times a week over four weeks. Additional experiments generated AD cell models with OAβ1-42, STZ, or mature TauP301L in primary hippocampal neurons and SH-SY5Y cells. CIR and AD pathology-related behavioral and biomarker assessments were performed. RESULTS: RIC intervention reduces CIR, β-amyloid (Aβ) and Tau pathology. Additionally, RIC improves anxiety-like, depression-like behaviors and cognitive impairments in sAD rats. Mechanistically, it increases peripheral/central IGF1 levels, activates the IGF1R/IRS1-AKT-GSK3β pathway in sAD/fAD models, and enhances GLUT1-AMPK pathway for glucose metabolism. Additionally, RIC boosts antioxidative and anti-apoptotic responses by modulating FOXO3a phosphorylation and nuclear translocation. In vitro, IGF1 administration mirrored RIC's protective effects against OAβ1-42, TauP301L, or STZ administration. CONCLUSIONS: Findings show that RIC effectively inhibits CIR by enhancing the IGF1R/IRS1-AKT-GSK3β pathway and glucose-mitochondrial energy metabolism. This study identifies a novel RIC neuroprotective mechanism, offering a multi-target AD prevention/treatment strategy.