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

Leng, Lige; Yuan, Ziqi; Pan, Rui‐Yuan; Su, Xiao; Wang, Han; Xue, Jin; Zhuang, Kai; Gao, Ju; Chen, Zhenlei; Lin, Hui-Kuan; Xie, Wenting; Li, Huifang; Chen, Zhenyi; Ren, Keke; Zhang, Xiao; Wang, Wenting; Wu, Sihan; Wang, Xinglong; Yuan, Zengqiang; Xu, Huaxi; Chow, Hei Man; Zhang, Jie

doi:10.1038/s42255-022-00643-4

Cited by 42 publications

(48 citation statements)

References 67 publications

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“…Prominent elevation of HK2 in DAM, by promoting glycolytic flux, may help microglia meet elevated demands for energy and precursor production in driving both microgliosis and inflammation in diseases. In addition, a recent study by Leng et al 53 also showed that HK2 is elevated in microglia in both AD mouse models and patients, thus providing another angle on how HK2 is involved in the activation of microglia 53 . HK2 inhibition enhanced lipid metabolism to promote microglial phagocytosis, thereby facilitating the clearance of amyloid plaque and attenuating cognitive impairment in AD mice 53 .…”

Section: Hexokinase 2 As a Unique Glycolytic Gatekeeper In Microgliamentioning

confidence: 98%

“…In addition, a recent study by Leng et al 53 also showed that HK2 is elevated in microglia in both AD mouse models and patients, thus providing another angle on how HK2 is involved in the activation of microglia 53 . HK2 inhibition enhanced lipid metabolism to promote microglial phagocytosis, thereby facilitating the clearance of amyloid plaque and attenuating cognitive impairment in AD mice 53 .…”

Section: Hexokinase 2 As a Unique Glycolytic Gatekeeper In Microgliamentioning

confidence: 98%

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Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

Cao

Wang

et al. 2022

Nat Metab

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Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about the metabolic determinants in microglia. By mining large datasets and generating transgenic tools, here we show that hexokinase 2 (HK2), the most active isozyme associated with mitochondrial membrane, is selectively expressed in microglia in the brain. Genetic ablation of HK2 reduced microglial glycolytic flux and energy production, suppressed microglial repopulation, and attenuated microglial surveillance and damage-triggered migration in male mice. HK2 elevation is prominent in immune-challenged or disease-associated microglia. In ischaemic stroke models, however, HK2 deletion p ro mo ted n eu ro in fl am mation and potentiated cerebral damages. The enhanced inflammatory responses after HK2 ablation in microglia are associated with aberrant mitochondrial function and reactive oxygen species accumulation. Our study demonstrates that HK2 gates both glycolytic flux and mitochondrial activity to shape microglial functions, changes of which contribute to metabolic abnormalities and maladaptive inflammation in brain diseases.Metabolism has emerged as a key regulator in both innate and adaptive immunity 1 . Microglia, the primary immune cells and key guardians of brain activity in the brain, adopt different metabolic states in response to exogenous stimuli 2-4 . For example, pro-inflammatory microglia utilize aerobic glycolysis to promote synthesis of inflammatory cytokines, whereas immunomodulatory microglia in mice increase fatty acid metabolism to drive anti-inflammatory responses 2,3 . Moreover, metabolic dysfunction of microglia has been implicated in multiple diseases including Alzheimer's disease (AD) and chronic demyelination disease models [4][5][6] . Microglia deficient in triggering the receptor expressed on

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Section: Hexokinase 2 As a Unique Glycolytic Gatekeeper In Microgliamentioning

confidence: 98%

Section: Hexokinase 2 As a Unique Glycolytic Gatekeeper In Microgliamentioning

confidence: 98%

Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

Cao

Wang

et al. 2022

Nat Metab

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“…Furthermore, it was recently found that hexokinase (HK) 2, the rate limiting enzyme in glucose metabolism, is a negative regulator of microglial LPL. Genetic ablation of HK2 in microglia increases the level of triglycerides and LPL, which stimulates free fatty acid metabolism to produce ATP, leading to Aβ uptake and improved cognitive functions in a mouse model of AD ( Leng et al, 2022 ). HFD itself was found to increase hypothalamic microglia Lpl gene expression too.…”

Section: Neuroinflammationmentioning

confidence: 99%

“…Impaired microglial phagocytosis was recently shown to be stimulated by elevated level of HK2 in AD mice and humans. Deletion or inhibition of HK2 lowers the level of Aβ by enhancing phagocytosis and clearance of Aβ by microglia, eventually improving AD pathology and cognitive function ( Leng et al, 2022 ). Downregulation of HK2 is thought to facilitate phagocytosis by stimulating Lpl expression.…”

Section: Neuroinflammationmentioning

confidence: 99%

“…Downregulation of HK2 is thought to facilitate phagocytosis by stimulating Lpl expression. Microglia LPL was further shown to promote phagocytosis of Aβ, by allowing the cells to produce ATP, thus providing sufficient fuel for this energy-demanding process ( Leng et al, 2022 ). TREM2 is another regulator of Lpl , and has also been thought to regulate efferocytosis/phagocytosis.…”

Section: Neuroinflammationmentioning

confidence: 99%

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The diverse roles of macrophages in metabolic inflammation and its resolution

Ray

Odum

Wiseman

et al. 2023

Front. Cell Dev. Biol.

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Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions–insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.

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Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

Gedam,

Zheng

2024

Eur J Immunol

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the C3a receptor (C3aR), covering its structure, ligand‐receptor interaction, intracellular signaling and its functional consequences. Drawing insights from cellular and AD mouse model studies, we present the multifaceted role of complement C3aR signaling in AD and attempt to convey to the readers that C3aR acts as a crucial immune and metabolic modulator to influence AD pathogenesis. Building on this framework, the objective of this review is to inform future research endeavors and facilitate the development of therapeutic strategies for this challenging condition.

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

Cited by 42 publications

References 67 publications

Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

The diverse roles of macrophages in metabolic inflammation and its resolution

Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

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