Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

Czirr, Eva; Castello, Nicholas A.; Mosher, Kira Irving; Castellano, Joseph M.; Hinkson, Izumi V.; Lucin, Kurt M.; Baeza-Raja, Bernat; Ryu, Jae K.; Li, Lulin; Farina, Sasha N.; Belichenko, Nadia P.; Longo, Frank M.; Akassoglou, Katerina; Britschgi, Markus; Cirrito, John R.; Wyss‐Coray, Tony

doi:10.1084/jem.20162011

Cited by 103 publications

(86 citation statements)

References 68 publications

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“…Increasing evidence suggested that activated microglia is a key causative factor in in ammation-mediated neurodegeneration and behavior de cits [42]. Dys-regulated microglial activation is reported to be able to increase pathological protein aggregation and impair synaptic pruning and neuron plasticity in key brain regions sub-serving cognition [43,44]. In the present study, activated microglia were detected in the hippocampus and cortex of rotenone-induced mouse PD model.…”

Section: Discussionsupporting

confidence: 55%

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

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Section: Discussionsupporting

confidence: 55%

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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“…*Note that CD59 is an inhibitor of complement pathway activity, so the synapse/neuron loss seen with CD59 knockout is consistent with a beneficial effect of reducing complement activation. Reference (Ref) 1, Fonseca et al, 2004 ; Ref 2, Hong et al, 2016 ; Ref 3, Fonseca et al, 2017 ; Ref 4, Shi et al, 2015 ; Ref 5, Shi et al, 2017a ; Ref 6, Maier et al, 2008 ; Ref 7, Wyss-Coray et al, 2002 ; Ref 8, Czirr et al, 2017 ; Ref 9, Fonseca et al, 2009 ; Ref 10, Olmos-Alonso et al, 2016 ; Ref 11, Spangenberg et al, 2016 ; Ref 12, Britschgi et al, 2012 ; and Ref 13, Asai et al, 2015 . FB (FD, FH, FI), complement factor B (D, H, I); KO, knockout; MASP, MBL-associated serine protease; MBL, mannose-binding lectin.…”

Section: Detrimental Activities Of Microglia In Admentioning

confidence: 99%

Microglia in Alzheimer’s disease

Hansen¹,

Hanson²,

Sheng³

2017

Journal of Cell Biology

1,339

1,029

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“…Fu and colleagues have shown that APP/PS1 mice treated with the cytokine IL-33 present lower levels of pro-inflammatory gene expression (i.e., IL-1β , IL-6 , NLRP3 ) in association with reduced Aβ load, increased magnitude of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, and improved cognitive function [ 99 ]. Blockage of mediators of the complement cascade, including C1q [ 100 ], C3 [ 101 , 102 ], and C5a [ 103 ], also confers neuroprotective effects in mouse models of AD. Moreover, deficiency of IκB kinase β, which activates NF-κB, in microglia reduces inflammatory activation and Aβ load in the brain of TgCRND8-APP mice, effects which are associated with a reduction in cognitive deficits and preservation of synaptic structural proteins [ 104 ].…”

Section: The Complexity Of Pro- and Anti-inflammatory Timingmentioning

confidence: 99%

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Newcombe

Camats-Perna

Silva

et al. 2018

J Neuroinflammation

417

302

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Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

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Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

Abstract: Czirr et al. report that microglia lacking complement receptor 3 display increased extracellular Aβ degrading activity and that targeting the receptor with a small molecule increases Aβ clearance in vivo, thus identifying a microglial receptor as a novel therapeutic target.

Cited by 103 publications

References 68 publications

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Microglia in Alzheimer’s disease

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

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