Nat Metab Zhang's team revealed a new mechanism of glycolipid metabolism regulation in microglia, providing a new strategy for the prevention and treatment of Alzheimer's disease

Editor-in-Charge | Alzheimer's disease (AD) is a major neurodegenerative disease that seriously threatens human health, and it is expected that there will be more than 70 million AD patients worldwide in 2030, placing a heavy burden on
patients, families and society.
The pathogenesis of AD is complex, and there is still a lack of effective therapeutic drugs, so it is urgent to elucidate new pathogenic mechanisms of AD and discover new therapeutic targets
.
AD is also known as "type 3 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 in the glucose metabolism pathway responsible for intracellular glucose metabolism is hexokinase (HK), responsible for converting glucose to glucose
6-phosphate.
There are four members of the HK family, of which HK1-3 is expressed in the central nervous system, but little is
known about its function in the brain.

Professor Zhang Jie's team and collaborators of Xiamen University published an article 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 development of type 2 diabetes and AD [1].

Follow-up studies have found that HK2 is not only expressed in neurons, but also in microglia
.
Microglia are immune cells in the brain that have a great demand
for ATP energy supply.
Metabolic disorders can directly lead to abnormal microglial function, leading to and exacerbating the development
of many neurological diseases, especially neurodegenerative diseases.
In-depth disclosure of microglial metabolism regulation and energy supply mechanism has a very important role
in understanding the pathogenic mechanism of AD and prevention and treatment.

On October 6, 2022, the team of Professor Jie Zhang of the Institute of Neuroscience of Xiamen University School of Medicine published a report titled Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid in the journal Nature Metabolism Clearance's research results
.
Reveal the effect and mechanism
of hexokinase 2 (HK2) regulating the transition of sugar-lipid metabolism on ATP energy, phagocytosis and inflammation of microglia.
It was found that the tumor clinical drug HK2 inhibitor clonidamine can significantly improve the production of ATP in microglia and clear amyloid deposition, and improve the role of cognitive dysfunction in AD mice, providing a new strategy
for the prevention and treatment of AD.


The paper 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 expressed specifically in AD patients and AD mouse microglia
.
The researchers constructed microglia HK2-specific knockout mice and crossed them with AD mice
.
The knockout of HK2 in microglia significantly promoted the phagocytosis of amyloid by microglia and alleviated the cognitive impairment of AD mice
.
As an important kinase for glucose metabolism, HK2's activity regulation plays an important role in tumorigenesis and development[2].

The HK2 kinase inhibitor Lonidamine has been clinically used in the treatment
of a variety of tumors.
Zhang Jie's team found that the administration of clonidamine to the ventricles or abdominal cavity can significantly promote the phagocytic of amyloid by glial cells in AD mice and improve cognitive dysfunction
in AD mice.
As a clinically safer drug, chlornidamine may be used as a drug for the prevention and treatment of AD
.
The figure below shows a small dose of chlornidamine injection in the ventricles that can remove amyloid deposits
from the brains of AD mice within 48 hours.


In terms of regulatory mechanism, Zhang Jie's team found that although the knockout or inhibition of HK2 inhibited the use of glucose by microglia, by upregulating the key enzyme of lipid metabolism, lipoprotein lipase (LPL), the lipid metabolism in microglia was mobilized, the level of intracellular ATP was raised very quickly, and the phagocytic function
of microglia was promoted 。 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-diphosphate does not
.
Further mechanism studies have found that G-6-P and F-6-P can regulate lipid metabolism
through the pentase phosphate pathway.
These results closely link glycospid-lipid metabolism to microglial function, including phagocytosis
.
This work showed that the short-term, periodic inhibition of glucose metabolism in microglia can promote the phagocytic effect
of microglia on amyloid.
At the same time, the researchers also found that this effect is unique to microglia, and the inhibition of glucose metabolism does not increase ATP production
in other types of brain cells, such as neurons and astrocytes.
This work elucidated a new mechanism of microglia glycolipid metabolism regulation, and expanded a new strategy
for the prevention and treatment of AD and other neurodegenerative diseases based on microglial metabolism regulation.


At the same time, it is worth mentioning that Zhang Jie's team and the Yuan Qiangqiang team of the Academy of Military Medical Sciences recently elucidated the epiregulatory mechanism of PKM2 in microglia metabolism remodeling in AD (Cell Metabolism, 2022)[3].

Both HK2 and PKM2 are key regulatory enzymes for glucose metabolism, and this series of studies helps to systematically understand the mechanism of action of
microglia metabolic reprogramming in the pathogenesis of AD.

Professor Jie Zhang and Associate Professor Leng Lige of the Institute of Neuroscience, School of Medicine, Xiamen University are the corresponding authors
of this paper.
At the same time, Associate Professor Leng Lige is the first author
of this paper.

Original link:

https://doi.
org/10.
1038/s42255-022-00643-4

Plate Maker: Eleven

References

1.
Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence.
Chow HM, Shi Meng, Cheng A, Gao Y, Chen G, Song X, So RWL, Jie Zhang*, Karl Herrup*.
Nature Neuroscience.
2019 Nov; 22(11):1806-1819.
2.
Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey B, Hay N.
Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.
Cancer Cell.
2013 Aug 12; 24(2):213-228

3.
Pan RY, He L, Zhang J, Liu X, Liao Y, Gao J, Liao Y, Yan Y, Li Q, Zhou X, Cheng J, Xing Q, Guan F, Zhang J, Sun L, Yuan Z.
Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease.
Cell Metab.
2022 Apr 5; 34(4):634-648.
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