Cognitive impairment remains one of the most challenging aspects of neuroscience, intricately linked to a complex network of cellular interactions and biochemical pathways. Groundbreaking recent research now sheds light on a crucial, yet often overlooked, component of brain health: the metabolic interplay between microglia and neurons. These brain-resident immune cells, traditionally viewed solely as defenders against pathogens, emerge as vital partners in sustaining cognitive functions through their metabolic activities. This evolving understanding compels a reevaluation of neuroimmune interactions, presenting a dynamic perspective on how cellular metabolism shapes brain resilience and cognitive prowess in both normal physiology and disease contexts.
At the core of this paradigm lies microglia, whose functions extend far beyond immune surveillance. During brain development, the metabolic pathways within microglia and neurons coordinate to orchestrate synaptic pruning, neuronal growth, and network refinement. The metabolic crosstalk ensures that microglia can respond appropriately to neuronal signals, modulating energy utilization to support neurogenesis and synaptic plasticity. This fine-tuned metabolic symbiosis crucially influences the establishment of functional neural circuits foundational for cognition.
In adult brains, this microglia-neuron metabolic axis continues to play a pivotal role, sustaining cognition by regulating neuroinflammation and neuronal energy demands. Microglia adapt their metabolic states dynamically, switching between glycolysis and oxidative phosphorylation depending on the neural environment and the organism’s systemic metabolic status. Such plasticity guarantees that the brain can maintain homeostasis and adapt to fluctuating physiological conditions without compromising cognitive integrity.
However, the story takes a darker turn with ageing. Here, the tightly regulated metabolic communication between microglia and neurons deteriorates, leading to increased neuroinflammatory signaling and impaired energy metabolism. Age-associated mitochondrial dysfunction in microglia fosters a pro-inflammatory phenotype that disrupts neuronal metabolic support. Consequently, cognitive decline ensues, highlighting cellular metabolism as a cornerstone of neurodegeneration pathways. These findings suggest that metabolic dysregulation within the neuroimmune milieu is a key culprit behind the cognitive deficits observed in elderly populations.
Moreover, metabolic disorders such as diabetes mellitus further exacerbate this dysfunction. Hyperglycemia-induced oxidative stress and systemic inflammation reverberate in the brain’s microenvironment, perturbing microglial metabolism and neuronal energy homeostasis. These alterations create a vicious cycle, amplifying neuroinflammatory responses and impairing synaptic function. The mechanistic insights confirm that peripheral metabolic health is intricately linked to central nervous system functionality, emphasizing the need for integrated therapeutic strategies.
Neuroinflammatory diseases illustrate another facet of this metabolic interdependence. Conditions like multiple sclerosis and Alzheimer’s disease exhibit characteristic metabolic shifts within microglia, including altered lipid metabolism and impaired autophagy. Such changes not only influence microglial activation states but also directly compromise neuronal survival and synaptic integrity. Targeting these metabolic checkpoints holds promise for modulating disease progression by restoring immunometabolic balance.
Importantly, microglial metabolic pathways are finely tuned during brain development stages, involving key regulatory molecules such as mTOR and AMPK. These molecules act as metabolic sensors and orchestrators, integrating environmental cues and energy status to calibrate microglial functions. The downstream effects impact neurotrophic support and synaptic remodeling—processes integral to cognitive maturation and plasticity. Dissecting these pathways at a molecular level opens avenues for therapeutic modulation during critical developmental windows.
In parallel, neuronal metabolism itself undergoes modulation by microglial biochemical outputs. The release of metabolites and cytokines from microglia can enhance or suppress neuronal mitochondrial function, influencing the efficiency of ATP production required for neurotransmission and plasticity. This mutual metabolic regulation cements the concept of microglia not merely as immune sentinels but as metabolic partners essential for cognitive health.
Emerging technologies such as single-cell metabolomics and high-resolution imaging have been instrumental in unraveling these complex metabolic exchanges. These methodologies enable the visualization and quantification of metabolic fluxes and signaling molecules in situ, providing unprecedented resolution into microglia-neuron interactions. As a result, researchers can now chart temporal and spatial metabolic landscapes, correlating them directly with cognitive outcomes.
On the therapeutic front, metabolic interventions targeting microglial function are gaining increasing attention. Agents that modulate microglial metabolism, such as those activating mitochondrial biogenesis or promoting anti-inflammatory metabolic states, show potential in preclinical models to enhance cognitive resilience. Such strategies herald a new era in neurotherapeutics, moving beyond symptom management to precise metabolic reprogramming.
Furthermore, lifestyle factors influencing systemic metabolism, including diet and exercise, indirectly affect microglial metabolic states and neuronal function. Nutritional compounds with antioxidant and anti-inflammatory properties can recalibrate neuroimmune metabolism, underscoring the holistic nature of brain health management. This integrative perspective advocates for multifaceted approaches combining lifestyle modification with targeted pharmacological interventions.
Critically, understanding the bidirectional metabolic dialogue also offers insights into brain plasticity under stress and injury. During neuroinflammation or after trauma, microglial metabolic reprogramming dictates the balance between neuroprotection and neurotoxicity. Fine-tuning this balance could enhance recovery processes and mitigate long-term cognitive impairments.
The dynamic neuroimmune-metabolic interface also extends implications for cognitive disorders beyond classical neurodegeneration, including psychiatric illnesses where neuroinflammation and metabolic abnormalities coexist. Investigating microglia-neuron metabolic axes could unravel new pathological mechanisms and therapeutic targets in these domains.
As the field advances, it becomes clear that the metabolic engine driving cognition is not solely neuronal but is a collaborative output of neuron and microglia interaction. This recognition shifts paradigms, highlighting that maintaining metabolic harmony within this cellular duet is vital for sustaining cognitive function through life’s span and disease.
This comprehensive mechanistic understanding sets the stage for innovative research, inspiring the design of novel biomarkers and therapies aimed at fortifying the neuroimmune metabolic nexus. The convergence of immunology, metabolism, and neuroscience stands poised to revolutionize our approach to cognitive health, with far-reaching implications for ageing societies worldwide.
In conclusion, deciphering the intricacies of microglia-neuron metabolic interactions represents a frontier in neuroscience, offering hope for ameliorating cognitive impairment across a spectrum of disorders. By targeting the metabolic determinants of brain resilience, science moves closer to unlocking the full potential of cognitive longevity in both health and disease.
Subject of Research: Interactions between microglia and neurons focusing on metabolic pathways influencing cognition in health, ageing, and neurological diseases.
Article Title: The metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease.
Article References:
Asimakidou, E., Pluchino, S., Silva, B.A. et al. The metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01409-4
Image Credits: AI Generated
