Neuroglial Metabolic Crosstalk in Alzheimer Disease (AD): Mechanisms and Therapeutic Opportunities

Neuronal survival and synaptic function depend on tightly regulated metabolic cooperation between neurons and glial cells, rather than autonomous cellular energy production. Within the central nervous system, astrocytes, oligodendrocytes, and microglia coordinate the supply, transformation, and recycling of metabolic substrates that sustain axonal conduction, synaptic transmission, and cellular resilience under stress. Astrocytes act as primary metabolic buffers, channeling glucose derived carbon into lactate, lipids, and antioxidant precursors that support neuronal firing and plasticity. Oligodendrocytes provide long range metabolic support to myelinated axons through monocarboxylate transporter dependent lactate transfer, thereby preserving axonal integrity during sustained activity. Microglia integrate metabolic state with immune function, adjusting glycolytic and oxidative programs to regulate phagocytosis, cytokine production, and tissue remodeling.In Alzheimer’s disease, this coordinated metabolic architecture becomes progressively destabilized. Deficient glucose utilization and impaired astrocytic lactate supply contribute to synaptic failure and neuronal energy crisis. Altered lipid synthesis and transport within glial cells disrupt cholesterol homeostasis, promote amyloid beta aggregation, and accelerate tau pathology. Concurrently, redox imbalance arising from mitochondrial dysfunction and insufficient antioxidant buffering amplifies oxidative damage and sensitizes neurons to regulated cell death pathways, including ferroptosis.Beyond the brain, peripheral metabolic cues exert measurable influence on glial function. Microbiota derived short chain fatty acids, hepatic lipid signals, and adipose derived adipokines modulate glial metabolic programming and inflammatory tone, thereby shaping vulnerability to Alzheimer’s disease progression.This Research Topic seeks mechanistic and translational studies that define how glial metabolic networks are organized in health and how their failure drives Alzheimer’s disease pathology. Submissions are encouraged that interrogate human postmortem tissue, patient derived induced pluripotent stem cell systems, and genetically defined animal models to uncover metabolically tractable nodes that can be leveraged for therapeutic intervention. Integration of single nucleus transcriptomics with spatial metabolite profiling and systems level modeling is encouraged to resolve cell type specific metabolic states and identify predictive biomarkers linked to disease stage and treatment response.Key research areas of interest include but are not limited to:• Energy substrate coordinationDefine how astrocyte derived lactate, glucose metabolites, glycogen stores, and ketone bodies support neuronal and axonal metabolism under physiological conditions, and how disruption of these pathways contributes to synaptic dysfunction and cognitive decline in Alzheimer’s disease.• Lipid and cholesterol homeostasisExamine glial control of phospholipid, cholesterol, and sphingolipid synthesis, transport, and storage through APOE, ABCA1, and liver X receptor signaling, and determine how dysregulation promotes plaque formation, myelin instability, and neurotoxicity.• Redox balance and mitochondrial couplingElucidate how antioxidant systems, mitochondrial substrate utilization, and reactive oxygen species signaling are coordinated between glia and neurons, and how failure of these mechanisms accelerates protein aggregation and cell death.• Immuno-metabolic and systemic modulationCharacterize metabolic shifts in reactive glia, including transitions between glycolysis and fatty acid oxidation, and assess how peripheral metabolic signals from the gut, liver, and adipose tissue reshape glial inflammatory and metabolic states in Alzheimer’s disease.• Translational targeting and biomarker discoveryIdentify metabolically actionable pathways for therapeutic development, including glial metabolic imaging strategies and fluid-based biomarkers that reflect disease progression and therapeutic response, using integrated single cell metabolomics, multi omics analyses, and computational modeling. Topic editors: Nawab John Dar, Shahnawaz Ali Bhat Source: https://www.frontiersin.org/research-topics/77701/neuroglial-metabolic-crosstalk-in-alzheimer-disease-ad-mechanisms-and-therapeutic-opportunities