This hypothesis proposes that enhancing endogenous ketone body synthesis within astrocytes through targeted overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) will restore neuronal metabolic function in conditions of glucose hypometabolism. Unlike the typical hepatic ketogenesis pathway, astrocytic HMGCS2 upregulation would enable local β-hydroxybutyrate production within the brain parenchyma, creating a proximal fuel source for neighboring neurons. The mechanism involves astrocyte-specific viral vector delivery of HMGCS2, leading to increased acetyl-CoA conversion to ketone bodies within astrocytic mitochondria. These locally produced ketones would then be transported to neurons via existing monocarboxylate transporters, bypassing potential blood-brain barrier limitations and systemic ketosis requirements. This approach targets the rate-limiting step of ketogenesis directly within the CNS microenvironment, potentially providing more efficient and sustained neuronal fuel delivery compared to peripheral ketone supplementation or transport enhancement alone.

This hypothesis proposes that enhancing endogenous ketone body synthesis within astrocytes through targeted overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) will restore neuronal metabolic function in conditions of glucose hypometabolism. Unlike the typical hepatic ketogenesis pathway, astrocytic HMGCS2 upregulation would enable local β-hydroxybutyrate production within the brain parenchyma, creating a proximal fuel source for neighboring neurons. The mechanism involves astrocyte-specific viral vector delivery of HMGCS2, leading to increased acetyl-CoA conversion to ketone bodies within astrocytic mitochondria. These locally produced ketones would then be transported to neurons via existing monocarboxylate transporters, bypassing potential blood-brain barrier limitations and systemic ketosis requirements. This approach targets the rate-limiting step of ketogenesis directly within the CNS microenvironment, potentially providing more efficient and sustained neuronal fuel delivery compared to peripheral ketone supplementation or transport enhancement alone. The astrocyte-neuron metabolic coupling would be strengthened through this endogenous ketone production system, supporting neuronal ATP generation, reducing oxidative stress, and maintaining synaptic function during periods of glucose insufficiency. This strategy could be particularly beneficial in neurodegenerative diseases characterized by brain glucose hypometabolism, such as Alzheimer's disease, where astrocytic ketone production could compensate for impaired neuronal glucose utilization and provide neuroprotective effects through enhanced mitochondrial respiration and reduced inflammatory signaling.