Autophagy Balances Neuroinflammation in Alzheimer’s Disease

Cheng, Xuehua; Wei, Yong; Qian, Zijun; Han, Li

doi:10.1007/s10571-022-01269-6

Cited by 17 publications

(8 citation statements)

References 137 publications

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“…Autophagy is a highly evolutionary conserved degradation system that allows cells to rapidly eliminate various intracellular elements within eukaryotic cells [ 57 ]. The autophagy dysfunction, such as loss of the autophagy proteins, including BECN1, ATG5, or ATG16L1, contributes to excessive inflammation and hyper-activation of NLRP3 inflammasome [ 58 – 60 ], indicating the potential roles of autophagy in the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

Wang,

Li,

Lian

et al. 2024

Research

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As a key executioner of pyroptosis, Gasdermin D (GSDMD) plays a crucial role in host defense and emerges as an essential therapeutic target in the treatment of inflammatory diseases. So far, the understanding of the mechanisms that regulate the protein level of GSDMD to prevent detrimental effects and maintain homeostasis is currently limited. Here, we unveil that ubiquitin-specific peptidase 18 (USP18) works as a negative regulator of pyroptosis by targeting GSDMD for degradation and preventing excessive innate immune responses. Mechanically, USP18 recruits E3 ubiquitin ligase mind bomb homolog 2 (MIB2) to catalyze ubiquitination on GSDMD at lysine (K) 168, which acts as a recognition signal for the selective autophagic degradation of GSDMD. We further confirm the alleviating effect of USP18 on LPS-triggered inflammation in vivo. Collectively, our study demonstrates the role of USP18 in regulating GSDMD-mediated pyroptosis and reveals a previously unknown mechanism by which GSDMD protein level is rigorously controlled by selective autophagy.

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Section: Discussionmentioning

confidence: 99%

USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

Wang,

Li,

Lian

et al. 2024

Research

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“…Excessive p62 and LC3-positive vesicles accumulated in the brain region of temporal lobe cortex of AD patients, together with increased protein levels of LAMP1, a lysosomal maker. Further analysis indicated that these excessive autophagic vesicles are associated with activated NLRP3 inflammasome, Aβ aggregates and phosphorylated tau protein ( 127 ). Findings from a mouse line with microglia-specific Atg7 knockout indicated that microglia cells use autophagy to clear extracellular Aβ fibrils.…”

Section: Autophagy and Neuroinflammation In Neurodegenerative Diseasesmentioning

confidence: 99%

Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity

Bai,

Keyser,

Zhang

et al. 2024

Front. Immunol.

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Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins via the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders. Recent evidence reveals that dysregulated autophagy plays an important role in the initiation and progression of neuroinflammation, a common pathological feature in many neurological disorders leading to defective synaptic morphology and plasticity. In this review, we will discuss the regulation of autophagy and its effects on synapses and neuroinflammation, with emphasis on how autophagy is regulated by epigenetic mechanisms under healthy and diseased conditions.

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“…Chronic triggering of inflammasomes in the brain tissue leads to an increased level of IL-18 family cytokines [ 159 ]. Autophagy dysfunction may be associated with AD pathology, and autophagy activation may suppress neuroinflammation by degrading inflammasomes [ 160 ]. The development of small molecular autophagy inducers represents a pharmacological opportunity for the protection of neurons in AD [ 161 ].…”

Section: Conventional and Novel Targets For Slowing And/or Preventing...mentioning

confidence: 99%

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

Penke

Szücs

Bogár³

2023

IJMS

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Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research.

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Autophagy Balances Neuroinflammation in Alzheimer’s Disease

Cited by 17 publications

References 137 publications

USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D

Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

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