TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy

Bemiller, Shane M.; McCray, Tyler J.; Allan, Kevin; Formica, Shane; Xu, Guixiang; Wilson, Gina N.; Kokiko-Cochran, Olga N.; Crish, Samuel D.; Lasagna‐Reeves, Cristian A.; Ransohoff, Richard M.; Landreth, Gary E.; Lamb, Bruce T.

doi:10.1186/s13024-017-0216-6

Cited by 214 publications

(202 citation statements)

References 37 publications

(29 reference statements)

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“…Here, we show that variants within this AD risk locus modify CSF sTREM2 levels. Previous research has already suggested that changes in sTREM2 levels, or TREM2 biology in general, are likely involved in disease pathology (12)(13)(14)(15)(16)(17)(18)24). These MS4A variants also impact MS4A4A and MS4A6A expression in human blood and brain tissue, as previously reported (44,45).…”

Section: Discussionsupporting

confidence: 67%

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The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Deming¹,

Filipello²,

Cignarella³

et al. 2018

Preprint

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Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15×10−15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

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Section: Discussionsupporting

confidence: 67%

“…On the other hand, a common phenotype across mouse models of amyloidosis is that reduction or loss of Trem2 leads to fewer amyloid plaque-associated microglia (9,14,16). Other studies indicate that Trem2 deficiency protects against neurodegeneration through a dampened microglial-response to tau pathology (17,18).…”

Section: Introductionmentioning

confidence: 99%

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Deming¹,

Filipello²,

Cignarella³

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Pure Tauopathy models have also shown conflicting results when TREM2 was knocked out. TREM2 KO‐hTau mice were shown by one group to have increased pathology and neurodegeneration (Bemiller et al, ), while another group reported decreased neuroinflammation and decreased neurodegeneration in the PS19 Tau protein transgenic mouse model (Leyns et al, ). In a primary microglia–neuron co‐culture, Tau hyperphosphorylation was shown to result from LPS‐induced inflammation, suggesting that inflamed microglia can induce Tau pathology.…”

Section: Trem2mentioning

confidence: 99%

“…Pure Tauopathy models have also shown conflicting results when TREM2 was knocked out. TREM2 KO-hTau mice were shown by one group to have increased pathology and neurodegeneration (Bemiller et al, 2017), while another group reported decreased neuroinflammation and decreased neurodegeneration in the PS19…”

Section: Trem2 Loss-of-function Mutations Are Associated With Neuromentioning

confidence: 99%

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

Nizami

Hall-Roberts

Warrier

et al. 2019

British J Pharmacology

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One of the largest unmet medical needs is a disease‐modifying treatment for Alzheimer's disease (AD). Recently, the role of microglia in disease, particularly AD, has gained great interest, following the identification of several disease risk‐associated genes that are highly expressed in microglia. Microglia play a critical homeostatic role in the brain, with neuroinflammatory and phagocytic mechanisms being of particular importance. Here, we review the role of NLRP3, the complement system, and the triggering receptor expressed in myeloid cells 2 (TREM2) in modulating microglial functions. We have reviewed the targets, their molecular pathways and the therapeutic interventions aimed at modulating these targets, in the hope of discovering a novel therapeutic approach for the treatment of AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…A LOF mutation in the lipid sensing function, a minimotif activity of Trem2 deficient mice may be the underlying mechanism for the loss of microglia proliferation and microglial response to Aβ plaques or reduced infiltration of peripheral macrophages [251,252]. In addition, Trem2 deficiency leads to exacerbated aggregation of tau in a mouse model of tauopathy [253]. These findings demonstrate that TREM2 has complex multiple roles in regulating Aβ and tau pathologies that may reflect its distinct functions at different stages in AD pathology [254].…”

Section: Genetics and Epigenetics Of Minimotifs In Ndsmentioning

confidence: 86%

Minimotifs dysfunction is pervasive in neurodegenerative disorders

Sharma

Young²,

Chen

et al. 2018

A&D Transl Res & Clin Interv

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Minimotifs are modular contiguous peptide sequences in proteins that are important for posttranslational modifications, binding to other molecules, and trafficking to specific subcellular compartments. Some molecular functions of proteins in cellular pathways can be predicted from minimotif consensus sequences identified through experimentation. While a role for minimotifs in regulating signal transduction and gene regulation during disease pathogenesis (such as infectious diseases and cancer) is established, the therapeutic use of minimotif mimetic drugs is limited. In this review, we discuss a general theme identifying a pervasive role of minimotifs in the pathomechanism of neurodegenerative diseases. Beyond their longstanding history in the genetics of familial neurodegeneration, minimotifs are also major players in neurotoxic protein aggregation, aberrant protein trafficking, and epigenetic regulation. Generalizing the importance of minimotifs in neurodegenerative diseases offers a new perspective for the future study of neurodegenerative mechanisms and the investigation of new therapeutics.

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TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy

Cited by 214 publications

References 37 publications

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

Minimotifs dysfunction is pervasive in neurodegenerative disorders

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