Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liv...Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.展开更多
基金the Department of Biology at Syracuse University(to CHL)a start-up grant from the Department of Biomedical and Chemical Engineering at Syacuse University(to JZ)an NIH grant(R01DK141923)sub-contract to Co-Investigators JZ and CHL from the Principal Investigator Mark W.Grinstaff。
文摘Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.
