Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease

Lautrup, Sofie; Lou, Guofeng; Aman, Yahyah; Nilsen, Hilde; Tao, Jun; Fang, Evandro Fei

doi:10.1016/j.neuint.2019.104469

Cited by 83 publications

(62 citation statements)

References 30 publications

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“…Under physiological conditions, microglia play an important role in neuronal survival by producing neurotrophic factors as well as by phagocytosing dead cells, protein aggregates, cellular debris, and invading pathogens [2]. Accordingly, reduced phagocytotic activity of microglia may result in ADassociated neuroinflammation [3][4][5][6][7]. Microglia respond quickly to various stimuli.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

Zhu

Che

et al. 2020

J Neuroinflammation

111

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Background: Microglial activation is a prominent feature of neuroinflammation, which is present in almost all neurodegenerative diseases. While an initial inflammatory response mediated by microglia is considered to be protective, excessive pro-inflammatory response of microglia contributes to the pathogenesis of neurodegeneration. Although autophagy is involved in the suppression of inflammation, its role and mechanism in microglia are unclear. Methods: In the present study, we studied the mechanism by which lipopolysaccharide (LPS) affects microglial autophagy and the effects of autophagy on the production of pro-inflammatory factors in microglial cells by western blotting, immunocytochemistry, transfection, transmission electron microscopy (TEM), and real-time PCR. In a mouse model of neuroinflammation, generated by intraventricular injection of LPS (5 μg/animal), we induced autophagy by rapamycin injection and investigated the effects of enhanced autophagy on microglial activation by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Results: We found that autophagic flux was suppressed in LPS-stimulated N9 microglial cells, as evidenced by decreased expression of the autophagy marker LC3-II (lipidated form of MAP1LC3), as well as increased levels of the autophagy adaptor protein SQSTM1. LPS significantly decreased Vps34 expression in N9 microglial cells by activating the PI3KI/AKT/MTOR pathway without affecting the levels of lysosome-associated proteins and enzymes. More importantly, overexpression of Vps34 significantly enhanced the autophagic flux and decreased the accumulation of SQSTM1 in LPS-stimulated N9 microglial cells. Moreover, our results revealed that an LPS-induced reduction in the level of Vps34 prevented the maturation of omegasomes to phagophores. Furthermore, LPSinduced neuroinflammation was significantly ameliorated by treatment with the autophagy inducer rapamycin both in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

Zhu

Che

et al. 2020

J Neuroinflammation

111

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“…There was a fourfold increase in IL-10 levels in the hippocampal tissue of treated mice (Fang et al, 2019). Previously, it has been reported that IL-10 increases mitophagy in macrophages (Ip et al, 2017;Lautrup et al, 2019). It might be possible that in the case of UA and AC treatment, increased IL-10 further promotes mitophagy in microglia, though it needs further exploration.…”

Section: Mitophagy In Microgliamentioning

confidence: 85%

“…It has been observed that the efficiency of microglia to clear Aβ plaques reduces chronic inflammation and mitochondrial dysfunction. Restoring mitochondrial function and mitophagy in microglia helps reduce neuroinflammation and is therefore neuroprotective (Lautrup et al, 2019). Fang et al (2019) observed that there was an increase in damaged mitochondria in APP/PS1 mice, mouse models for AD, and a 60% reduction in mitophagy in the hippocampus of these mice with respect to WT mice.…”

Section: Mitophagy In Microgliamentioning

confidence: 99%

Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia

Agrawal

Jha

2020

Front. Aging Neurosci.

125

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In 1907, Alois Alzheimer observed, as he quoted, development of “numerous fibers” and “adipose saccules” in the brain of his diseased patient Auguste Deter. The neurodegenerative disease became known as Alzheimer’s disease (AD) and is the most common cause of dementia worldwide. AD normally develops with aging and is mostly initiated because of the imbalance between the formation and clearance of amyloid-β (Aβ). Formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau is another hallmark of AD. Neuroinflammation plays a significant role in the development and pathology of AD. This chapter explores the role of mitochondrial dysfunction in microglia in case of AD. Mitochondrial oxidative stress in microglia has been linked to the development of AD. Elevated generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential through various mechanisms have been observed in AD. Aβ interacts with microglial receptors, such as triggering receptor expressed in myeloid cells 2 (TREM2), activating downstream pathways causing mitochondrial damage and aggravating inflammation and cytotoxicity. Fibrillar Aβ activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia leading to elevated induction of mitochondrial ROS which further causes neurotoxicity. Elevated ROS in microglia causes activation of inflammatory and cell death pathways. Production of ATP, regulation of mitochondrial health, autophagy, and mitophagy in microglia play significant roles in the AD pathology. Understanding microglial physiology and mitochondrial dysfunction will enable better therapeutic interventions.

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“…294,295 This has led to great interest in AD therapeutics that promote mitophagy to eliminate impaired mitochondria. 296 In fact, boosting mitophagy has been shown to attenuate cognitive deficits and promote microglial phagocytosis of Aβ while decreasing neuroinflammation in APPPS1 AD mice. 297 An additional sex-specific factor involved in AD is the sexual dimorphism of microglia.…”

Section: Role Of Age Environmental Factors and Sex In Admentioning

confidence: 99%

The role of innate immunity in Alzheimer's disease

Ennerfelt

Lukens

2020

Immunological Reviews

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The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain‐resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.

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Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease

Cited by 83 publications

References 30 publications

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia

The role of innate immunity in Alzheimer's disease

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