This hypothesis proposes that enhancing ketone body synthesis specifically within astrocytes through overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) can restore neuronal metabolic homeostasis in neurodegenerative conditions. Unlike the typical hepatic ketogenesis pathway, astrocytes possess latent ketogenic capacity that becomes activated under metabolic stress. By genetically upregulating HMGCS2 in astrocytes using viral vectors or transgenic approaches, we can establish a local brain ketone production system that bypasses systemic metabolic limitations. The mechanism involves converting acetyl-CoA derived from fatty acid oxidation and amino acid catabolism into acetoacetate and β-hydroxybutyrate directly within the brain microenvironment. This local ketone production would provide neurons with an immediate alternative fuel source during glucose hypometabolism, particularly relevant in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions where neuronal glucose utilization is compromised.

This hypothesis proposes that enhancing ketone body synthesis specifically within astrocytes through overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) can restore neuronal metabolic homeostasis in neurodegenerative conditions. Unlike the typical hepatic ketogenesis pathway, astrocytes possess latent ketogenic capacity that becomes activated under metabolic stress. By genetically upregulating HMGCS2 in astrocytes using viral vectors or transgenic approaches, we can establish a local brain ketone production system that bypasses systemic metabolic limitations. The mechanism involves converting acetyl-CoA derived from fatty acid oxidation and amino acid catabolism into acetoacetate and β-hydroxybutyrate directly within the brain microenvironment. This local ketone production would provide neurons with an immediate alternative fuel source during glucose hypometabolism, particularly relevant in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions where neuronal glucose utilization is compromised. Enhanced astrocytic ketogenesis would create sustained ketone availability without relying on peripheral ketone transport across the blood-brain barrier or neuronal uptake mechanisms. The intervention targets the rate-limiting enzyme of ketogenesis, ensuring robust ketone body production. Evidence would be gathered through metabolomic profiling of brain tissue, measurement of ketone body concentrations in cerebrospinal fluid, assessment of neuronal ATP levels, and evaluation of cognitive/motor function in disease models. This approach shifts from facilitating ketone uptake to generating ketones locally, potentially providing more consistent and controllable neuroprotective benefits.