Complement C1q drives microglia-dependent synaptic loss and cognitive impairments in a mouse model of lipopolysaccharide-induced neuroinflammation

Wu, Xinmiao; Gao, Yu-Zhu; Shi, Cui-Na; Tong, Jian-hua; Ma, Daqing; Shen, Jin-Chun; Yang, Jianjun; Ji, Mu‐Huo

doi:10.1016/j.neuropharm.2023.109646

Cited by 25 publications

(8 citation statements)

References 61 publications

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“…A C1q-neutralization antibody reduces microglia-dependent synaptic loss and cognitive impairments in a mouse model of LPS-induced neuroinflammation ( Wu et al, 2023 ). Notably, a humanized anti-C1q antibody; ANX005 (immunoglobulin G4 recombinant anti-body) is now in Phase I clinical trials for the treatment of autoimmune and neurodegenerative diseases ( Lansita et al, 2017 ).…”

Section: Therapeutic Strategies To Attenuate Reactive Astrogliosis An...mentioning

confidence: 99%

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Rahman,

Islam,

Bhuiyan

2024

Front. Pharmacol.

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Cerebrovascular diseases and their sequalae, such as ischemic stroke, chronic cerebral hypoperfusion, and vascular dementia are significant contributors to adult disability and cognitive impairment in the modern world. Astrocytes are an integral part of the neurovascular unit in the CNS and play a pivotal role in CNS homeostasis, including ionic and pH balance, neurotransmission, cerebral blood flow, and metabolism. Astrocytes respond to cerebral insults, inflammation, and diseases through unique molecular, morphological, and functional changes, collectively known as reactive astrogliosis. The function of reactive astrocytes has been a subject of debate. Initially, astrocytes were thought to primarily play a supportive role in maintaining the structure and function of the nervous system. However, recent studies suggest that reactive astrocytes may have both beneficial and detrimental effects. For example, in chronic cerebral hypoperfusion, reactive astrocytes can cause oligodendrocyte death and demyelination. In this review, we will summarize the (1) roles of ion transporter cascade in reactive astrogliosis, (2) role of reactive astrocytes in vascular dementia and related dementias, and (3) potential therapeutic approaches for dementing disorders targeting reactive astrocytes. Understanding the relationship between ion transporter cascade, reactive astrogliosis, and cerebrovascular diseases may reveal mechanisms and targets for the development of therapies for brain diseases associated with reactive astrogliosis.

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Section: Therapeutic Strategies To Attenuate Reactive Astrogliosis An...mentioning

confidence: 99%

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Rahman,

Islam,

Bhuiyan

2024

Front. Pharmacol.

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“…This upregulation is accompanied by an increase in synaptic phagocytosis by microglial cells, resulting in a higher loss of synapses and subsequent cognitive impairment in the mice. However, it was observed that neutralizing C1q signaling can prevent these changes, suggesting that activated microglial cells and the complement cascade C1q signaling may play a role in the synaptic loss and cognitive impairment observed in the LPS-induced neuroinflammation mouse model [ 65 ]. In another study involving neurons and glial cells stimulated by LPS, the levels of C3 were also significantly increased, which can enhance LPS-induced neuroinflammation and neurodegeneration through the Mac1/NOX2 pathway [ 66 ].…”

Section: Main Bodymentioning

confidence: 99%

The complement system: a potential target for the comorbidity of chronic pain and depression

Tang,

Hu,

Zou

et al. 2024

Korean J Pain

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The mechanisms of the chronic pain and depression comorbidity have gained significant attention in recent years. The complement system, widely involved in central nervous system diseases and mediating non-specific immune mechanisms in the body, remains incompletely understood in its involvement in the comorbidity mechanisms of chronic pain and depression. This review aims to consolidate the findings from recent studies on the complement system in chronic pain and depression, proposing that it may serve as a promising shared therapeutic target for both conditions. Complement proteins C1q, C3, C5, as well as their cleavage products C3a and C5a, along with the associated receptors C3aR, CR3, and C5aR, are believed to have significant implications in the comorbid mechanism. The primary potential mechanisms encompass the involvement of the complement cascade C1q/C3-CR3 in the activation of microglia and synaptic pruning in the amygdala and hippocampus, the role of complement cascade C3/C3a-C3aR in the interaction between astrocytes and microglia, leading to synaptic pruning, and the C3a-C3aR axis and C5a-C5aR axis to trigger inflammation within the central nervous system. We focus on studies on the role of the complement system in the comorbid mechanisms of chronic pain and depression.

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“…Ahmad et al ( 2019 ) reported that repeated intraperitoneal injection of LPS (0.25 mg/kg/day for 7 days) strongly reduced hippocampal synapses measured by western blots 7 days later. Wu et al ( 2023 ) used a similar model, and found loss of hippocampal synapses due to C1q-dependent microglial phagocytosis of synapses, together with cognitive impairments detected by Y maze and novel object recognition testing. Note, however, that the extent of synapse loss and memory impairment varies with LPS species and serotype, and increases in aged mice (Beyer et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Much of the neurotoxicity of LPS in mice is known to be mediated by microglia (Fig. 5 ), via inducing either: microglial phagocytosis of synapses (Kondo et al, 2011 ; Weberpals et al, 2009 ; Manabe et al 2021 ; Cao et al 2021 ; Wu et al 2023 ), or phagocytosis of neurons (Neher et al 2011 ; Neher et al 2014 ; Milde et al 2021 ), or the neurotoxicity of microglial reactive oxygen or nitrogen species (Mander & Brown 2005 ; Qin et al 2013 ), or TAU hyperphosphorylation and aggregation in neurons (Li et al 2003 ; Quintanilla et al 2004 ; Ojala et al 2008 ; Bhaskar et al 2010 ; Ghosh et al 2013 ; Maphis et al 2015 ; Ising et al 2019 ). Microglia are known to specifically phagocytose neurons with TAU aggregates when alive, resulting in neuronal death and TAU spreading (Brelstaff et al 2018 ), and inhibition of microglial phagocytosis can reduce tauopathy in mice (Puigdellívol et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“… Response to LPS. The microglial and other cellular responses to LPS (or inflammation induced by LPS) can in principle be reduced by blocking: a) TLR4 (Rice et al 2010 ), b) complement activation or complement receptor 3 (Bodea et al 2014 ; Wu et al 2023 ), c) the P2Y6 receptor (Milde et al 2021 ; Puigdellívol et al 2021 ) or d) the inflammasome (Heneka et al 2018 ; Chen et al 2020 ). However, blocking TLR4 or these other targets may reduce innate immunity, so it is at present unclear whether this would be of net benefit in AD.…”

Section: Introductionmentioning

confidence: 99%

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The endotoxin hypothesis of Alzheimer’s disease

Brown,

Heneka

2024

Mol Neurodegeneration

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Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.

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Complement C1q drives microglia-dependent synaptic loss and cognitive impairments in a mouse model of lipopolysaccharide-induced neuroinflammation

Cited by 25 publications

References 61 publications

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

The complement system: a potential target for the comorbidity of chronic pain and depression

The endotoxin hypothesis of Alzheimer’s disease

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