Brain insulin resistance and microglial immunometabolic dysregulation in neurodegenerative diseases.

Brain insulin resistance (BIR) is increasingly recognized as a contributor to the development and progression of neurodegenerative diseases rather than simply a metabolic abnormality. In the central nervous system, insulin signaling is involved in neuronal survival, synaptic plasticity, energy metabolism, and protein homeostasis. Increasing evidence suggests that impaired brain insulin signaling is associated with Alzheimer disease (AD), Parkinson disease (PD), and other neurodegenerative conditions, although the mechanisms linking BIR to persistent inflammation and neuronal injury remain incompletely understood. Microglia, the principal innate immune cells of the central nervous system, integrate metabolic and immune signals and may therefore provide an important link between impaired insulin signaling and chronic inflammation. BIR may disrupt insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) signaling and promote nuclear factor-kappa B (NF-κB) activation, mitochondrial dysfunction, oxidative stress, impaired mitophagy, and lysosomal and lipid metabolic disturbances. These changes may promote activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory mediator release, excessive phagocytosis, and synaptic dysfunction. In turn, persistent microglial inflammation may further impair insulin signaling, forming a reciprocal feedback loop that sustains pathological changes. This review summarizes the mechanisms linking BIR to microglial immunometabolic dysfunction and discusses potential therapeutic strategies targeting metabolic and inflammatory pathways in neurodegenerative diseases.