A new mechanism for the regulation of glucose and lipid metabolism

Alzheimer's disease (AD) is a major neurodegenerative disease that seriously threatens human health. It is estimated that there will be more than 70 million AD patients worldwide in 2030, bringing a heavy burden to patients, families and society.

The pathogenic mechanism of AD is complex, and there is still a lack of effective therapeutic drugs. It is urgent to elucidate the new pathogenic mechanism of AD and discover new therapeutic targets. AD is also called "type III diabetes", and abnormal glucose metabolism plays an important role in the pathogenesis of AD. However, the mechanism is unclear, especially the role of glucose metabolism disorders in the central nervous system in the development of AD is still poorly understood.

The first key enzyme responsible for intracellular glucose metabolism in the glucose metabolism pathway is hexokinase (Hexokinase, HK), which is responsible for converting glucose into glucose 6-phosphate. There are four members of the HK family, among which HK1-3 are expressed in the central nervous system, but little is known about their functions in the brain. The related professor team published a paper in Nature Neuroscience in 2019, revealing that Hexokinase 2 (Hexokinase 2, HK2) plays an important role in insulin resistance leading to neuronal cell cycle restart and neuronal aging, revealing a new mechanism for the occurrence and development of type 2 diabetes and AD . Subsequent studies found that HK2 is not only expressed in neurons, but also has a high expression level in microglia. Microglia are immune cells in the brain and have a great demand for ATP energy supply. Metabolic disorders will directly lead to abnormal function of microglia, leading to and exacerbating the occurrence and development of many neurological diseases, especially neurodegenerative diseases. In-depth revelation of microglial metabolic regulation and energy supply mechanism plays a very important role in the understanding and prevention of AD pathogenesis.

In the research paper on October 6, 2022, the influence and mechanism of hexokinase 2 (HK2) regulating the transition of glucose-lipid metabolism on ATP energy supply, phagocytosis, and inflammation of microglia were revealed. It was also found that the clinical drug HK2 inhibitor lonidamine can significantly increase the ATP production of microglial cells and remove amyloid deposition, and improve the cognitive dysfunction of AD mice, which provides a new strategy for the prevention and treatment of AD .

The research team first systematically detected the expression of key molecules of glucose metabolism in the brains of AD mice. It was found that in the hexokinase family, only HK2 was specifically elevated in the microglia of AD patients and AD mice. The researchers constructed microglial HK2-specific knockout mice and crossed them with AD mice. Knockout of HK2 in microglia significantly promoted the phagocytosis of amyloid by microglia and alleviated the cognitive impairment in AD mice. HK2 is an important kinase in glucose metabolism, and its activity regulation plays an important role in the occurrence and development of tumors.

The HK2 kinase inhibitor Lonidamine has been clinically used in the treatment of various tumors. Zhang Jie's team found that intracerebroventricular or intraperitoneal administration of lonidamine can significantly promote the phagocytosis of amyloid by microglia in AD mice, and improve the cognitive dysfunction of AD mice. As a clinically safer drug, lonidamine may be used as a preventive drug for AD.

In terms of regulatory mechanism, the team found that although the knockout or inhibition of HK2 inhibited the utilization of glucose by microglia, it mobilized the lipid metabolism in microglia by up-regulating the key enzyme of lipid metabolism lipoprotein lipase (LPL). Rapidly increased the level of intracellular ATP and promoted the phagocytosis of microglia. Two downstream metabolites of HK2, glucose-6-phosphate (G-6-P) and fructose-6-phosphate (F-6-P), reverse this process, but fructose-1,6-bisphosphate does not have this effect. Further mechanistic studies found that G-6-P and F-6-P can regulate lipid metabolism through the pentose phosphate pathway.

These results tightly link glucose-lipid metabolism to microglial functions including phagocytosis. This work demonstrates that transient, periodic inhibition of glucose metabolism in microglia can promote amyloid phagocytosis by microglia. The researchers also found that this effect was specific to microglia, and that inhibition of glucose metabolism did not increase ATP production in other types of brain cells, such as neurons and astrocytes.