Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases

Bartels, Tim; Schepper, Sebastiaan De; Hong, Soyon

doi:10.1126/science.abb8587

Cited by 261 publications

(189 citation statements)

References 73 publications

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“…The molecular mechanisms by which microglia contributes to the pathogenesis of neurodegenerative diseases are the subject of intense investigations. Insight into these questions will enable not only the understanding of disease pathogenesis, but also the development of novel therapeutic strategies combating these disorders [38].…”

Section: Discussionmentioning

confidence: 99%

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

Chen

Aguzzi

et al. 2020

Preprint

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The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain, and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance, and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis.

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Section: Discussionmentioning

confidence: 99%

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

Chen

Aguzzi

et al. 2020

Preprint

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“…Microglial activation is a reliable indicator of pathological changes in α-synucleinopathies (Bartels et al, 2020;Choi et al, 2020;Kam et al, 2020). Pathological α-syn can induce the upregulation of ionized calcium-binding adapter molecule 1 (IBA-1) in hA53T mice, allowing discrimination between surveilling and activated microglia (Hopperton et al, 2018;Yun et al, 2018).…”

Section: Depletion Of Lag3 Decreases Glial Activation In Ha53t Micementioning

confidence: 99%

Lymphocyte Activation Gene 3 (Lag3) Contributes to α-Synucleinopathy in α-Synuclein Transgenic Mice

Yang

Mao

et al. 2021

Front. Cell. Neurosci.

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Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson’s disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.

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“…In addition, AD microglia associated with amyloid beta (Aβ) plaques demonstrate downregulation of genes involved in their normal function, including P2Y12, P2Y13, CX3CR1, CD33 and TMEM119; reduced mobility; phagocytic activity [94]; and decreased barrier function [32], while simultaneously upregulating genes that contribute to synaptic loss [34,95,96]. This has led to a prevailing hypothesis that decrease in microglial homeostatic functions contributes to AD pathogenesis.…”

Section: Contribution Of Glial Cells To Human Neurodegenerative Diseasesmentioning

confidence: 99%

Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator

Sheeler

Rosa

Ferro

et al. 2020

IJMS

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Over the past decade, research has unveiled the intimate relationship between neuroinflammation and neurodegeneration. Microglia and astrocytes react to brain insult by setting up a multimodal inflammatory state and act as the primary defenders and executioners of neuroinflammatory structural and functional changes. Microglia and astrocytes also play critical roles in the maintenance of normal brain function. This intricate balance of homeostatic and neuroinflammatory functions can influence the onset and the course of neurodegenerative diseases. The emergent role of the microglial-astrocytic axis in neurodegenerative disease presents many druggable targets that may have broad therapeutic benefits across neurodegenerative disease. Here, we provide a brief review of the basal function of both microglia and astrocytes, how they are changed in disease states, the significant differences between mouse and human glia, and use of human induced pluripotent stem cells derived from patients to study cell autonomous changes in human astrocytes and microglia.

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Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases

Cited by 261 publications

References 73 publications

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

Lymphocyte Activation Gene 3 (Lag3) Contributes to α-Synucleinopathy in α-Synuclein Transgenic Mice

Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator

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