2. Academic Validation
  3. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance

Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance

  • Nat Metab. 2022 Oct 6. doi: 10.1038/s42255-022-00643-4.
Lige Leng 1,  Ziqi Yuan 2,  Ruiyuan Pan 3,  Xiao Su 2,  Han Wang 2,  Jin Xue 2,  Kai Zhuang 2,  Ju Gao 4,  Zhenlei Chen 2,  Hui Lin 2,  Wenting Xie 2,  Huifang Li 2,  Zhenyi Chen 5,  Keke Ren 6,  Xiao Zhang 7,  Wenting Wang 6,  Zi-Bing Jin 7,  Shengxi Wu 6,  Xinglong Wang 4,  Zengqiang Yuan 3,  Huaxi Xu 2,  Hei-Man Chow 8,  Jie Zhang 9 10 11
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. lenglige@xmu.edu.cn.
  • 2 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
  • 3 The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 4 Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
  • 5 Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
  • 6 Department of Neurobiology, School of Basic Medicine, Fourth Military Medcial University, Xi'an, Shaanxi, China.
  • 7 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing, China.
  • 8 School of Life Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
  • 9 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China. jiezhang@xmu.edu.cn.
  • 10 Department of Anesthesiology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. jiezhang@xmu.edu.cn.
  • 11 Institute of Neuroscience, Fujian Medical University, Fuzhou, China. jiezhang@xmu.edu.cn.
PMID: 36203054 DOI: 10.1038/s42255-022-00643-4
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.

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