Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders

Abstract

Neuroimmunometabolism is an emerging field that examines the intersection of immunologic and metabolic cascades in the brain. Neuroinflammatory conditions often involve differential metabolic reprogramming in neuronal and glial cells through their immunometabolic sensors. The impact of such bioenergetic adaptation on general brain function is poorly understood, but this cross-talk becomes increasingly important in neurodegenerative disorders that exhibit reshaping of neuroimmunometabolic pathways. Here we summarize the intrinsic balance of neuroimmunometabolic substrates and sensors in the healthy brain and how their dysregulation can contribute to the pathophysiology of various neurodegenerative disorders. This review also proposes possible avenues for disease management through neuroimmunometabolic profiling and therapeutics to bridge translational gaps and guide future treatment strategies.SIGNIFICANCE STATEMENT Neuroimmunometabolism intersects with neuroinflammation and immunometabolic regulation of neurons and glial cells in the CNS. There is emerging evidence that neuroimmunometabolism plays an essential role in the manifestation of CNS degeneration. This review highlights how neuroimmunometabolic homeostasis is disrupted in various neurodegenerative conditions and could be a target for new therapeutic strategies.

Keywords: immunometabolic sensors; neurodegeneration; neuroimmunometabolism; neuroinflammation.

Figure 1.

Predominant neuroimmunometabolic homeostasis in the healthy brain and its disruption in neurodegenerative conditions. In the healthy state (left, blue arrows), glucose, amino acid, and lipid metabolism occur in various cell types. Neuroimmunometabolism disrupts this homeostasis (right, red arrows) contributing to degenerative conditions. IDO, Indoleamine-2,3 dioxygenase; PI3K/AKT, phosphoinositide 3-kinases.

Figure 2.

Major neuroimmunometabolic imbalances in neurodegenerative disorders. Several glucose, peptide, and lipid metabolic pathways are hindered in neurons and glia in these neurodegenerative diseases. These perturbations potentiate altered synthesis and transportation of different metabolites, leading to excitotoxicity, impaired phagocytosis, and inflammation in the CNS.

Figure 3.

Novel therapeutic strategies to control immunometabolic machinery in neurodegenerative disorders. Glucose analogs, inhibitors of GLUT1 and TCA-cycle enzymes, act on essential regulators to sustain or control glycolytic homeostasis in the brain. While bioguanides and mTOR inhibitors control glucose metabolism, JAK inhibitors and A1BP maintain cholesterol homeostasis and associated neuroinflammation. Immuno-nutraceutics, such as ketogenic diet, antioxidants, vitamins, and glutamine supplements, can also influence neuroinflammatory events in neurodegenerative conditions by fulfilling the brain's energy requirements through alternative metabolic pathways.