D-chiro-inositol modulates brain insulin-related signaling and reduces amyloid burden, neuroinflammation and cognitive decline in preclinical models of Alzheimer's disease

Brain metabolic dysregulation and insulin-related signaling are increasingly recognized as contributing factors in Alzheimer’s disease (AD) pathogenesis, disrupting amyloid-beta (Aβ) proteostasis and exacerbating neuroinflammation, and synaptic failure. However, current therapies yield inconsistent results due to a singular focus on specific targets, bioavailability and safety risks. D -chiro-inositol (DCI) is a natural compound with insulin-mimetic properties that has previously shown promising anti-inflammatory and neuroprotective results. This study investigated the neuroprotective efficacy of DCI using a tripartite approach: physiologically relevant primary neurons derived from App NL-G-F knock-in mice, human hAPPswe SH-SY5Y cells, and the aggressive 5xFAD mouse model of AD. Toxicity, pharmacokinetic and pharmacodynamic profiling established DCI’s safety and its ability to acutely improve systemic glucose handling. In vitro , DCI enhanced basal AKT and insulin receptor activation and modulated glycogen synthase kinase-3 beta (GSK-3β) activation, a kinase linked to amyloid precursor protein (APP) processing. This modulation was accompanied by reduced secretion of toxic Aβ42 species, preservation of neuronal integrity as determined by MAP2 immunostaining, and decreased overall APP protein levels. In vivo , chronic oral DCI administration significantly reduced hippocampal amyloid burden and promoted a shift in microglia from a reactive to a surveilling phenotype, with stronger effects in females. Notably, while DCI resolved microglial reactivity, astrogliosis remained largely unaffected, suggesting a cell-specific immunometabolic mechanism. These improvements translated into rescued recognition memory and normalized disinhibited risk-assessment behavior, indicative of restored hippocampal function. Collectively, DCI acts as a multi-modal agent by modulating insulin-related signaling, downregulating amyloid burden and attenuating neuroinflammation, making it an orally bioavailable candidate for AD therapy.