The Evolving Biology of Microglia in Alzheimer's Disease

Malm, Tarja; Jay, Taylor R.; Landreth, Gary E.

doi:10.1007/s13311-014-0316-8

Cited by 67 publications

(55 citation statements)

References 163 publications

(187 reference statements)

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“…Pathological changes in AD consist of Ab accumulation, tau phosphorylation and synaptic and neuronal loss, which develop steadily over years to decades in the context of a chronic and non-resolving pro-inflammatory response. Recent genome-wide association studies (GWAS) and systems biology approaches have confirmed a central role for the microglial inflammatory response in AD development (Lambert et al 2009(Lambert et al , 2013Augustin et al 2011;Hollingworth et al 2011;Naj et al 2011;Cruchaga et al 2013;Guerreiro et al 2013aGuerreiro et al , 2013bZhang et al 2013;Jiang et al 2014;Luo et al 2014;Gjoneska et al 2015), and support the hypothesis that maladaptive inflammatory responses play a central role in the pre-clinical development of AD (Heneka et al 2015;Malm et al 2015;Mhatre et al 2015).…”

Section: Conclusion and Controversiesmentioning

confidence: 93%

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Andreasson

Bachstetter

Colonna

et al. 2016

Journal of Neurochemistry

113

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Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer’s disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer’s disease are further contributions to this series.

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Section: Conclusion and Controversiesmentioning

confidence: 93%

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Andreasson

Bachstetter

Colonna

et al. 2016

Journal of Neurochemistry

113

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“…Activated microglia result in Aβ accumulation by enhancing the production of Aβ peptides and reducing its phagocytosis and degradation (22). Along with recruiting monocytes to lesion sites, IL-33 acts as an alarmin for the polarization of macrophages toward the alternative phenotype after CNS injury (42).…”

Section: Discussionmentioning

confidence: 99%

“…Because the Aβ phagocytic activity of microglia directly impacts Aβ clearance (22,23), we examined whether Aβ phagocytosis and degradation by resident microglia/infiltrating monocytes are altered in APP/PS1 mouse brains following IL-33 administration. To mediate Aβ phagocytic uptake, myeloid cells are first recruited to amyloid plaques before being activated and phagocytosing Aβ (8,24).…”

mentioning

confidence: 99%

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Hung

Yuen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

294

285

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Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.innate immunity | synaptic plasticity | β-amyloid | microglia | neuroninflammation

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“…Dysregulation of microglia functions contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) (6–8), Parkinson’s disease (PD) (9–12) and Huntington’s disease (HD) (13–15). In addition, microglia may play roles in neurodevelopmental and psychiatric diseases such as autism, schizophrenia (Scz) and depression (16, 17).…”

mentioning

confidence: 99%

An environment-dependent transcriptional network specifies human microglia identity

Gosselin

Skola

Coufal

et al. 2017

Science

997

1,158

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Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and following transition to an in vitro environment. Transfer to a tissue culture environment results in rapid and extensive downregulation of microglia-specific genes that are induced in primitive mouse macrophages following migration into the fetal brain. Substantial subsets of these genes exhibit altered expression in neurodegenerative and behavioral diseases and are associated with non-coding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human disease.

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The Evolving Biology of Microglia in Alzheimer's Disease

Cited by 67 publications

References 163 publications

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Targeting innate immunity for neurodegenerative disorders of the central nervous system

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

An environment-dependent transcriptional network specifies human microglia identity

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