Glycogen-Dependent Metabolic Reprogramming Regulates Microglial Activation and Dysfunction in Neurodegenerative Disease

From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases

Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.

The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.

Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging‐Associated Neurodegenerative Diseases

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes—including chronic low‐grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases—all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini‐review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex‐specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.

Astrocyte Lipid Metabolism: From Physiological Homeostasis to Reactive Phenotype Plasticity in Neurodegeneration.

Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.

Astrocyte lipid metabolism in brain health and neurodegeneration: from regulatory hub to maladaptive stressor

Neurodegenerative diseases are increasingly recognized as multicellular pathologies in which astrocytes serve as active determinants of disease onset and progression. Central to the regulatory role of astrocytes is the precise and dynamic control of brain lipid homeostasis. This review discusses a framework positioning astrocytic lipid metabolism as a key axis of both brain metabolic health and neurodegenerative processes. Under physiological conditions, astrocytes operate as the primary lipid metabolic hub, coordinating de novo cholesterol synthesis, APOE-mediated lipid transport, and the uptake and degradation of fatty acids. However, upon aging, chronic stress, and proteinopathies, these homeostatic programs undergo profound adaptation and remodeling. We detail how the breakdown of astrocytic lipid handling—driven by genetic risk factors such as APOE4 and manifesting as cholesterol dyshomeostasis, aberrant lipid droplet accumulation, impaired lipid turnover, and pro-inflammatory lipid signaling—transforms astrocytes into maladaptive reactive states and contributes to neurodegeneration. This metabolic rewiring not only deprives vulnerable neurons of essential metabolic and structural support but actively amplifies neuroinflammation and neurotoxicity. Finally, we consider therapeutic strategies aimed at restoring functional lipid flux and mitigating lipid-driven pathogenic signaling. By examining neurodegeneration through the lens of astrocytic lipid metabolism, we highlight novel conceptual paradigms for understanding neurodegeneration and emerging translational opportunities for disease interventions.

Astrocytic lipid dysregulation as an early driver of neurodegeneration