TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease

Rayaprolu, Sruti; Mullen, Bianca; Baker, Matt; Lynch, Timothy; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen‐Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol F.; Josephs, Keith A.; Knopman, David S.; White, Charles L.; Caselli, Richard J.; Mackenzie, Ian R.; Miller, Bruce L.; Boczarska-Jedynak, Magdalena; Opala, Grzegorz; Krygowska‐Wajs, Anna; Barcikowska, Maria; Younkin, Steven G.; Petersen, Ronald C.; Ertekin-Taner, Nilüfer; Uitti, Ryan J.; Meschia, James F.; Boylan, Kevin B.; Boeve, Bradley F.; Graff‐Radford, Neill R.; Wszołek, Zbigniew K.; Dickson, Dennis W.; Rademakers, Rosa; Ross, Owen A.

doi:10.1186/1750-1326-8-19

Cited by 347 publications

(286 citation statements)

References 19 publications

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“…Firstly, p.R62H TREM2 variant appears to be a risk factor for DLB (P = 0.0024, OR;3.2 [95% CI 1.7-27]). This variant was previously reported in association with AD (Jin et al 2014), and although these findings need replication, these observations further emphasize the overlapping genetic etiology of DLB and AD and endorse the view that TREM2 increases the risk of developing several neurodegenerative diseases (Rayaprolu et al 2013). Second, we show the first association of GRN variants with DLB.…”

Section: Discussionsupporting

confidence: 74%

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

et al. 2016

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Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.

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Section: Discussionsupporting

confidence: 74%

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

et al. 2016

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“…Guerreiro, et al, 2013b,R.J. Guerreiro, et al, 2013,Jonsson, et al, 2013,Le Ber, et al, 2014,Rayaprolu, et al, 2013 represents the most direct evidence to date that immune functions can modulate the course of these diseases. According to the currently prevailing view, loss-of-function mutations in TREM2 may result in unconstrained protein aggregate deposition and accelerate progression of these diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Guerreiro, et al, 2013a,R.J. Guerreiro, et al, 2013,Le Ber, et al, 2014,Rayaprolu, et al, 2013,Thelen, et al, 2014), Parkinson's disease (PD) (Rayaprolu, et al, 2013), and sporadic amyotrophic lateral sclerosis (ALS) (Cady, et al, 2014). These findings raise the question whether the dysregulation of crucial immunological functions associated with TREM2 variants may be a general causative factor in a broad spectrum of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. | P a g e AbstractDysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly upregulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2 -/-mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation, but does not noticeably modulate the pathogenesis of experimental prion infections.

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“…The same variant is a risk factor for Parkinson's disease (PD) and sporadic amyotrophic lateral sclerosis (ALS) (50,51). The R47H variant impairs TREM2 lipid recognition (52).…”

Section: Discussionmentioning

confidence: 99%

TREM2 sustains microglial expansion during aging and response to demyelination

Poliani¹,

Wang²,

Fontana³

et al. 2015

J. Clin. Invest.

410

428

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Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter

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TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease

Cited by 347 publications

References 19 publications

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

TREM2 sustains microglial expansion during aging and response to demyelination

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