Abstract
Alzheimer's disease (AD) is an aging-related neurodegenerative disorder. It is characterized clinically by progressive memory loss and impaired cognitive function. Its progression occurs from neuronal synapse loss to amyloid pathology and Tau deposit which eventually leads to the compromised neuronal function. Neurons in central nervous tissue work in a composite and intricate network with the glia and vascular cells. Microglia and astrocytes are becoming the prime focus due to their involvement in various aspects of neurophysiology, such as trophic support to neurons, synaptic modulation, and brain surveillance. AD is also often considered as the sequela of prolonged metabolic dyshomeostasis. The neuron and glia have different metabolic profiles as cytosolic glycolysis and mitochondrial-dependent oxidative phosphorylation (OXPHOS), especially under dyshomeostasis or with aging pertaining to their unique genetic built-up. Various efforts are being put in to decipher the role of mitochondrial dynamics regarding their trafficking, fission/fusion imbalance, and mitophagy spanning over both neurons and glia to improve aging-related brain health. The mitochondrial dysfunction may lead to activation in various signaling mechanisms causing metabolic reprogramming in glia cells, further accelerating AD-related pathogenic events. The glycolytic-dominant astrocytes switch to the neurotoxic phenotype, i.e., disease-associated astrocyte under metabolic stress. The microglia also transform from resting to reactive phenotype, i.e., disease-associated microglia. It may also exist in otherwise a misconception an M1, glycolytic, or M2, an OXPHOS-dependent phenotype. Further, glial transformation plays a vital role in regulating hallmarks of AD pathologies like synapse maintenance, amyloid, and Tau clearance. In this updated review, we have tried to emphasize the metabolic regulation of glial reactivity, mitochondrial quality control mechanisms, and their neuroinflammatory response in Alzheimer’s progression.
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Kumari Preeti is thankful to the Department of Pharmacology and Toxicology, NIPER Hyderabad and Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India.
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Research fellowship by National Institute of Pharmaceutical Education and Research, NIPER Hyderabad and Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India.
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Preeti, K., Sood, A. & Fernandes, V. Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease. Cell Mol Neurobiol 42, 2527–2551 (2022). https://doi.org/10.1007/s10571-021-01147-7
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DOI: https://doi.org/10.1007/s10571-021-01147-7