Brain Insulin Signaling Pathway Regulation of Hippocampal Neuroplasticity in Neurocognitive Disorders: Mechanisms and Therapeutic Implications.

Abstract

Neurocognitive disorders represent a significant global health challenge and are characterized by progressive cognitive decline across conditions including Alzheimer's disease, mild cognitive impairment, and diabetes-related cognitive impairment. The hippocampus is essential for learning and memory and requires intact neuroplasticity to maintain cognitive function. Recent evidence has identified the brain insulin signaling pathway as a key regulator of hippocampal neuroplasticity through multiple cellular processes including synaptic plasticity, neurotransmitter regulation, and neuronal survival. Dysregulation of this pathway contributes substantially to the pathophysiology of cognitive dysfunction in various disorders. Mechanistically, insulin modulates hippocampal neuroplasticity primarily through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascades, both of which promote synaptic plasticity and support neurogenesis. Beyond its neuronal effects, insulin signaling also regulates glial and endothelial cell function, orchestrating a coordinated multicellular response that is critical for hippocampal integrity. Emerging therapeutic approaches that target this pathway include intranasal insulin administration, glucagon-like peptide-1 (GLP-1) receptor agonists, and peroxisome proliferator-activated receptor (PPAR) agonists. These have demonstrated promising efficacy in restoring hippocampal function and improving cognitive outcomes in both preclinical and clinical studies. This review synthesizes current knowledge on the relationship between brain insulin signaling and hippocampal neuroplasticity. In addition, we highlight the therapeutic potential of insulin-targeted interventions for neurocognitive disorders, including quantifiable outcomes and sex-specific considerations.