Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease

Li, Yun; Xia, Xiaohuan; Wang, Yi; Zheng, Jialin

doi:10.1186/s12974-022-02613-9

Cited by 69 publications

(28 citation statements)

References 136 publications

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“…Microglia, which are innate immune cells of CNS, play a vital role in clearing pathogenic molecules and mediating the neuroinflammatory reaction [ 26 , 66 ]. Under pathological conditions, PAMP or DAMP induces the activation of microglia and NLRP3 inflammasome and resulting in neuroinflammation [ 34 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…Microglial activation-induced neuroinflammation is one of the important mechanisms underlying the pathogenesis of AD [ 26 , 70 , 71 ]. Several lines of evidence suggest that mitochondrial malfunction of microglia induces microglial activation and is involved in AD pathogenesis [ 66 ]. The accumulation of Aβ within mitochondria causes mitochondrial dysfunction and oxidative stress [ 70 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

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TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

Chen

Chang

Lee

et al. 2023

IJMS

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Translocase of outer mitochondrial membrane 40 (TOMM40) is located in the outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

Chen

Chang

Lee

et al. 2023

IJMS

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“…Interestingly, the most deregulated metabolites in the cortex of Pde2a +/− mice (glutathione and purine metabolism) are well known to contribute to oxidative stress (62). Recent studies have suggested that mitochondrial dysfunction, including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control disorders, precedes microglial activation and subsequent neuroinflammation (63). In this context, mitochondrial alterations may be associated with microglial activation.…”

Section: Discussionmentioning

confidence: 99%

Defects in AMPAR trafficking and microglia activation underlie socio-cognitive deficits associated to decreased expression of Phosphodiesterase 2A

Delhaye,

Jarjat,

Boulksibat

et al. 2023

Preprint

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Phosphodiesterase 2A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cortex and hippocampus, PDE2A expression level is upregulated inFmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygousPDE2Amutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized herePde2a+/−mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels.Pde2a+/−females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of GluR1 in CA1, producing reduced mGluR-dependent LTD. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer Disease, schizophrenia, FXS as well as other forms of ASD.

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“…The pro-inflammatory microglia can significantly alter energy metabolism in the brain, leading to impaired neuronal network function and blood-brain barrier dysfunction [70]. Pathophysiology in which changes in specific proteins lead to dysfunction in a number of different cellular pathways, including mitochondrial dysfunction, excitotoxicity, synaptic dysfunction, damage to protein degradation systems, ER stress, DNA damage, inflammation, and increased levels of reactive oxygen species (ROS) due to cell cycle re-entry [71], which in turn lead to the production of AD.…”

Section: 11admentioning

confidence: 99%

Advances in the study of the role of extraoral bitter taste receptors

Zhen

Fang

et al. 2023

Preprint

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Taste is one of the basic senses of living organisms and can recognize sour, bitter, salty, sweet and umami tastes. Bitter taste receptor is a class of G protein-coupled receptors capable of sensing bitterness. Initially, bitter taste receptor was thought to be only found in the taste buds of the tongue, palate and throat. Recent research has shown that in addition to the oral cavity, the bitter taste receptor is also present in the intestinal tract, respiratory tract, urinary tract, vascular smooth muscle, nervous system, thyroid gland and other tissues and organs to regulate body homeostasis and resist disorders . In this review, we focus on the effects of the bitter taste receptor outside the oral cavity to lay the groundwork for future research.

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Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease

Cited by 69 publications

References 136 publications

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease

Defects in AMPAR trafficking and microglia activation underlie socio-cognitive deficits associated to decreased expression of Phosphodiesterase 2A

Advances in the study of the role of extraoral bitter taste receptors

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