Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement

Guerreiro, Rita; Lohmann, Ebba; Brás, José; Gibbs, J. Raphael; Rohrer, Jonathan D.; Gurunlian, Nicole; Dursun, Burcu; Bılgıç, Başar; Hanağası, Haşmet; Gürvıt, Hakan; Emre, Murat; Singleton, Andrew B.; Hardy, John

doi:10.1001/jamaneurol.2013.579

Cited by 304 publications

(252 citation statements)

References 25 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…Guerreiro, et al, 2013a,R. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, TREM2 variants were also found to be associated with frontotemporal dementia-like syndrome or FTD (Borroni, et al, 2014,R. 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).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Trem2 is a scavenger receptor found on the surface of myeloid cells, and TREM2 mutations leading to impaired phagocytic activity [39] are strong risk factors for multiple neurodegenerative diseases, including ALS [26,36,10].…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Recent studies identified a rare TREM2 rs75932628 variant (p.R47H) as a risk factor for AD, suggesting that the protein plays an important role in neurodegeneration [6,19,20]. Studies also identified the association with diseased risk for frontotemporal dementia (FTD) [16] and ALS [15].…”

Section: Discussionmentioning

confidence: 99%

Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population

Chen¹,

Chen²,

Wei

et al. 2015

Journal of the Neurological Sciences

View full text Add to dashboard Cite

Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement

Cited by 304 publications

References 25 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

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

Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population

Contact Info

Product

Resources

About