TREM2 sustains microglial expansion during aging and response to demyelination

Poliani, Pietro Luigi; Wang, Yaming; Fontana, Elena; Robinette, Michelle L.; Yamanishi, Yoshihiro; Gilfillan, Susan; Colonna, Marco

doi:10.1172/jci77983

Cited by 401 publications

(477 citation statements)

References 59 publications

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“…Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2).…”

supporting

confidence: 81%

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Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

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supporting

confidence: 81%

“…Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2).…”

supporting

confidence: 81%

Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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“…It has previously been reported that TREM2 is capable of binding microbial and damage-associated molecular signatures found on bacteria (41,42), lipids exposed during axonal injury (23,43), and nucleic acid released from dying cells (29). Here, we report apoE as a novel TREM2 ligand.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 69%

“…Therefore, during experimental conditions that mimic microbial invasion or neural tissue damage, microglial TREM2 is able to bind bacterial fragments (41,42), anionic, zwitterionic, and myelin-associated lipids (23,43), and nucleic acid released from dead cells (29).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Atagi

Liu

Painter

et al. 2015

Journal of Biological Chemistry

436

435

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Background: TREM2 is associated with several neurodegenerative diseases. Results: ApoE bound to TREM2 and increased phagocytosis of apoptotic neurons by microglia. Alzheimer disease (AD) risk-associated TREM2-R47H mutant had a reduced binding to apoE. Conclusion: ApoE is a novel ligand for TREM2. Interaction between apoE and TREM2 likely regulates phagocytosis of apoEbound apoptotic neurons. Significance: Interaction between two AD risk-associated proteins modulates microglial function.

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“…However, recent work demonstrated that loss of Trem2 leads either to microglial degeneration in different diseases of the central nervous system [55,66,11], or conversely to protection [34]. Thus, the exact mechanisms underlying 5-HT 2B R-mediated regulation of microglial survival and the role of scavenger receptors in this response will have to be investigated in further studies.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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TREM2 sustains microglial expansion during aging and response to demyelination

Cited by 401 publications

References 59 publications

Age-related myelin degradation burdens the clearance function of microglia during aging

Age-related myelin degradation burdens the clearance function of microglia during aging

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

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