TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia

Kim, Su Man; Mun, Bo Ram; Lee, Sun Jun; Joh, Yechan; Lee, Hwa Youn; Ji, Kon Young; Choi, Hyungsub; Lee, Eun Hee; Kim, Eun Mi; Jang, Ji Hye; Song, Hyeong Woo; Mook‐Jung, Inhee; Choi, Won Seok; Kang, Hyung Sik

doi:10.1038/s41598-017-11634-x

Cited by 91 publications

(68 citation statements)

References 32 publications

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“…Despite the in vitro and in vivo evidence, the role of sTREM2 in the development of AD is still in dispute. Most researchers hold sTREM2 exerts a neuroprotective effect by improving the clearance effect of microglia [128], whereas sTREM2 can also trigger microglia to release pro-inflammatory cytokines, which may adversely affect neuronal function [129]. Studies have also reported that different body fluids, such as the CSF and blood, contain different levels of sTREM2 at different stages of AD progression [11].…”

Section: Discussionmentioning

confidence: 99%

TREM2 ectodomain and its soluble form in Alzheimer’s disease

Yang

Zhang

et al. 2020

J Neuroinflammation

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Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor mainly expressed on the surface of microglia. It mediates multiple pathophysiological processes in various diseases. Recently, TREM2 has been found to play a role in the development of Alzheimer's disease (AD). TREM2 is a transmembrane protein that is specifically expressed on microglia in the brain. It contains a long ectodomain that directly interacts with the extracellular environment to regulate microglial function. The ectodomain of TREM2 is processed by a disintegrin and metalloprotease, resulting in the release of a soluble form of TREM2 (sTREM2). Recent studies have demonstrated that sTREM2 is a bioactive molecule capable of binding ligands, activating microglia, and regulating immune responses during the AD continuum. Clinical studies revealed that sTREM2 level is elevated in cerebrospinal fluid (CSF) of AD patients, and the sTREM2 level is positively correlated with the levels of classical CSF biomarkers, namely t-tau and p-tau, indicating that it is a reliable predictor of the early stages of AD. Herein, we summarize the key results on the generation, structure, and function of sTREM2 to provide new insights into TREM2-related mechanisms underlying AD pathogenesis and to promote the development of TREM2-based therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

TREM2 ectodomain and its soluble form in Alzheimer’s disease

Yang

Zhang

et al. 2020

J Neuroinflammation

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“…Furthermore, we provide evidence that the number of Cd36 + microglia was significantly increased in frontal cortices of aged mice. Recently, increased expression of the scavenger receptor Cd36 in microglia was linked to triggering receptor expressed on myeloid cells 2 (Trem2)-mediated alleviations of AD symptoms by enhanced uptake of Aβ and abrogation of memory loss [ 35 ]. Moreover, lack of Cd36 exacerbated injury in cerebral ischemia models associated with reduced engulfment of apoptotic neurons and enhanced Nf-κB signaling [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions

Zöller

Attaai

Potru

et al. 2018

IJMS

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Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent changes in cortical microglia gene expression patterns and the expression of M1- and M2-like activation markers. Iba1 immunohistochemistry, isolation of cortical microglia followed by fluorescence-activated cell sorting and RNA isolation to analyze transcriptional changes in aged cortical microglia was performed. We provide evidence that aging is associated with decreased numbers of cortical microglia and the establishment of a distinct microglia activation profile including upregulation of Ifi204, Lilrb4, Arhgap, Oas1a, Cd244 and Ildr2. Moreover, flow cytometry revealed that aged cortical microglia express increased levels of Cd206 and Cd36. The data presented in the current study indicate that aged mouse cortical microglia adopt a distinct activation profile, which suggests immunosuppressive and immuno-tolerogenic functions.

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“…APP/PS1-TYROBP −/− mice display a reduction in the prevalence of Aβ oligomers and microglial activation compared to APP/PS1-TYROBP +/+ mice, indicating that a reduction in TREM2 signaling leads to beneficial effects in an AD mouse model [ 183 ]. Kim and colleagues recently found that TREM2 knockout was sufficient to cause the formation of endogenous murine Aβ plaques, and showed that TREM2 promotes the phagocytosis of Aβ by upregulating CD36 in microglia [ 184 ]. These data make it clear that TREM2 has a significant role in the clearance of abnormal protein deposits, although the mechanism by which this occurs has yet to be identified.…”

Section: The Genetic Risk Factors For Ad Are Involved In the Inflammamentioning

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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TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia

Cited by 91 publications

References 32 publications

TREM2 ectodomain and its soluble form in Alzheimer’s disease

TREM2 ectodomain and its soluble form in Alzheimer’s disease

Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions

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

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