Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Thelen, M.; Razquín, Cristina; Hernández, Isabel; Gorostidi, Ana; Sánchez‐Valle, Raquel; Ortega‐Cubero, Sara; Wolfsgruber, Steffen; Drichel, Dmitriy; Fließbach, Klaus; Duenkel, Tanja; Damian, Marinella; Heilmann, Stefanie; Slotosch, Anja; Lennarz, Martina; Seijo-Martínez, Manuel; Rizzoli, René; Kornhuber, Johannes; Peters, Oliver; Luckhaus, Christian; Jahn, Holger; Hüll, Michael; Rüther, Eckart; Wiltfang, Jens; Lorenzo, Elena; Gascón, Jordi; Lleó, Alberto; Lladó, Albert; Campdelacreu, Jaume; Moreno, Fermín; Ahmadzadehfar, Hojjat; Fortea, Juan; Indakoetxea, Begoña; Heneka, Michael T.; Wetter, Axel; Pastor, María A.; Riverol, Mario; Becker, Tim; Frölich, Lutz; Tárraga, Lluís; Boada, Merçé; Wagner, Michael; Jessen, Frank; Maier, Wolfgang; Clarimón, Jordi; Munáin, Adolfo López de; Ruiz, Agustín; Pástor, Pau; Ramı́rez, Alfredo

doi:10.1016/j.neurobiolaging.2014.06.018

Cited by 38 publications

(40 citation statements)

References 32 publications

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“…These findings have spurred numerous studies addressing the association between TREM2 and AD and other neurodegenerative diseases. Although negatives have been reported (Jiao, et al, 2014,Miyashita, et al, 2014,Ruiz, et al, 2014,Yu, et al, 2014, the association between TREM2 variants and AD has been confirmed by most studies (Benitez, et al, 2013,Giraldo, et al, 2013,Gonzalez Murcia, et al, 2013,Luis, et al, 2014,Slattery, et al, 2014. Moreover, TREM2 variants were also found to be associated with frontotemporal dementia-like syndrome or FTD (Borroni, et al, 2014,R.…”

Section: Introductionmentioning

confidence: 91%

“…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%

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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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Section: Introductionmentioning

confidence: 91%

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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“…Heterozygous expression of TREM2 variants has also been linked to cases of FTD, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) [79][80][81][82]. However, other studies have not found any TREM2 association with these neurodegenerative diseases, and it remains unclear whether TREM2 variants in the heterozygous state contribute to risk of neurodegenerative diseases other than AD [62,[83][84][85].…”

Section: Box 1 Plaque-associated Myeloid Cells: Identity and Impactmentioning

confidence: 99%

TREM2, Microglia, and Neurodegenerative Diseases

Yeh¹,

Hansen²,

Sheng³

2017

Trends in Molecular Medicine

330

271

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“…However, more recently a rare variant (p.R47H) in TREM2 was identified as a risk factor for ET in a Spanish population and this gene may turn out to be a promising candidate in other populations as well. A rare amino acid substitution (p.R47H; rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: 605086) has been identified as a risk factor for several neurodegenerative diseases, including Alzheimer disease (Jonsson et al, 2013; Ruiz et al, 2014), Parkinson disease (Benitez et al, 2013), fronto-temporal dementia (Ruiz et al, 2014; Thelen et al, 2014), and amyotrophic lateral sclerosis (Cady et al, 2014). A large cross-sectional multicenter international study that included a discovery ET case-control cohort from Spain ( n = 456 ET and n = 2715 controls) and a replication case-control series from different populations (Italy, Germany, North America, and Taiwan; n = 897 ET and n = 1449 controls) reported a significant association between TREM2 p.R47H and ET in the Spanish cohort (odds ratio (OR), 5.97; 95% confidence interval, 1.2–29.6; p = 0.042).…”

Section: Modes Of Inheritance and Transmission In Essential Tremormentioning

confidence: 99%

Essential tremor

Clark

Louis

2018

Neurogenetics, Part I

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Essential tremor (ET) is one of the most common neurologic disorders, and genetic factors are thought to contribute significantly to disease etiology. There has been a relative lack of progress in understanding the genetic etiology of ET. This could reflect a number of factors, including the presence of substantial phenotypic and genotypic heterogeneity. Thus, a meticulous approach to phenotyping is important for genetic research. A lack of standardized phenotyping across studies and patient centers likely has contributed to the relative lack of success of genomewide association studies in ET. To dissect the genetic architecture of ET, whole-genome sequencing will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. A number of approaches still remain unexplored in ET genetics, including the contribution of copy number variants, uncommon moderate-effect alleles, rare variant large-effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes, and noncoding variation.

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Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Cited by 38 publications

References 32 publications

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

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, Microglia, and Neurodegenerative Diseases

Essential tremor

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