Hypometabolism as a therapeutic target in Alzheimer's disease

Abstract

The pathology of Alzheimer's disease (AD) is characterized by cerebral atrophy in frontal, temporal, and parietal regions, with senile plaques, dystrophic neurites, and neurofibrillar tangles within defined areas of the brain. Another characteristic of AD is regional hypometabolism in the brain. This decline in cerebral glucose metabolism occurs before pathology and symptoms manifest, continues as symptoms progress, and is more severe than that of normal aging. Ketone bodies are an efficient alternative fuel for cells that are unable to metabolize glucose or are 'starved' of glucose. AC-1202 is designed to elevate serum ketone levels safely. We previously showed that treatment with AC-1202 in patients with mild-to-moderate AD improves memory and cognition. Treatment outcomes were influenced by apolipoprotein E genotype status. These data suggest that AC-1202 may be an effective treatment for cognitive dysfunction by providing an alternative substrate for use by glucose-compromised neurons.

Figure 1

Ketones overcome hypometabolism.

Figure 2

Metabolism of AC-1202 (MCTs) versus LCTs. MCTs are emulsifed in the gut lumen, where gastrointestinal lipases hydrolyze them to MCFAs. MCFAs are absorbed directly into the portal vein and, unlike LCT, are not packaged into lipoproteins. In the liver, MCFAs are quickly oxidized, whereas the fate of LCFAs is dependent on the metabolic state of the organism. LCFAs are transported to the mitochondria for oxidation using CPT1. When conditions favor fat storage, malonyl-CoA is produced as an intermediate in lipogenesis. Malonyl-CoA inhibits CPT1, and prevents oxidation of LCFAs in the mitochondria. MCFAs enter the mitochondria without the use of CPT1 and are not subject to the regulations that control the oxidation of LCFAs. Because MCFAs enter the liver rapidly and are quickly oxidized, a large oral dose of MCT will result in sustained hyperketonemia. CoA, coenzyme A; CPT1, carnitine palmitoyltransferase I; LCDG, diglyceride; LCFA, long-chain fatty acid; LCMG, long-chain monoglyceride; LCT, long-chain triglyceride; MCFA, medium-chain fatty acid; MCT, medium-chain triglyceride; TG, triglyceride.