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Updated: Aug 26, 2025
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
Published on: January 31, 2019
Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance
Lige Leng1, Ziqi Yuan2, Ruiyuan Pan3
1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. lenglige@xmu.edu.cn.
Abstract:
Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic β-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.
Insights
Hexokinase 2 (HK2) elevates in Alzheimer's disease (AD) microglia, impairing their ability to clear amyloid plaques. Inhibiting HK2 enhances microglial phagocytosis and improves cognitive function in AD mice.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglial cells are crucial for clearing neurotoxic aggregates like β-amyloid in Alzheimer's disease (AD).
- Microglial phagocytosis requires adenosine triphosphate (ATP), but the role of energy metabolism in AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of hexokinase 2 (HK2) in microglial energy metabolism and function in Alzheimer's disease (AD).
- To explore HK2 as a potential therapeutic target for AD.
Main Methods:
- Examined HK2 expression in microglia from 5xFAD AD mouse models and human AD patients.
- Utilized genetic deletion and pharmacological inhibition of HK2 in male AD mice.
- Assessed microglial phagocytosis, amyloid plaque burden, cognitive function, ATP levels, and lipoprotein lipase (LPL) expression.
Main Results:
- HK2 was found to be elevated in microglia of AD models and patients.
- Inhibiting or deleting HK2 significantly enhanced microglial phagocytosis of β-amyloid.
- HK2 inhibition led to increased ATP levels, upregulated LPL expression, and improved cognitive function in male AD mice.
- Specific HK2 metabolites (glucose-6-phosphate and fructose-6-phosphate) reversed HK2-deficiency effects on LPL and phagocytosis.
Conclusions:
- HK2 plays a critical role in regulating microglial energy metabolism and phagocytic capacity in AD.
- Targeting HK2 presents a promising therapeutic strategy for enhancing microglial function and treating Alzheimer's disease.
