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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.

Nature Metabolism
|October 6, 2022
PubMed

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.

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