TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

Kleinberger, Gernot; Yamanishi, Yoshihiro; Suárez‐Calvet, Marc; Czirr, Eva; Lohmann, Ebba; Cuyvers, Elise; Struyfs, Hanne; Pettkus, Nadine; Wenninger-Weinzierl, Andrea; Mazaheri, Fargol; Tahirović, Sabina; Lleó, Alberto; Alcolea, Daniel; Fortea, Juan; Willem, Michael; Lammich, Sven; Molinuevo, José Luís; Sánchez‐Valle, Raquel; Antonell, Anna; Ramı́rez, Alfredo; Heneka, Michael T.; Sleegers, Kristel; Zee, Julie van der; Martin, Jean‐Jacques; Engelborghs, Sebastiaan; Demirtaş-Tatlıdede, Aslı; Zetterberg, Henrik; Broeckhoven, Christine Van; Gürvıt, Hakan; Wyss‐Coray, Tony; Hardy, John; Colonna, Marco; Haass, Christian

doi:10.1126/scitranslmed.3009093

Cited by 667 publications

(928 citation statements)

References 49 publications

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“…Therefore, loss-of-function mutations in TREM2 may lead to unimpeded protein aggregate deposition and result in progression of the respective diseases. Indeed, missense TREM2 mutations associated with FTD and FTD-like syndrome were found to reduce TREM2 protein maturation, thereby abolishing its shedding by ADAM proteases and impairing the phagocytic activity of TREM2-expressing cells (Kleinberger, et al, 2014). However, others reported that the depletion of one allele of TREM2 in the APPPS1 mouse model did not affect Aβ deposition, even if TREM2 heterozygosity altered the microglial response in these mice (Ulrich, et al, 2014).…”

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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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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“…Loss of TREM2 function reduces the ability of microglia to engulf Aβ (15). AD patients with the TREM2 variant of R47H showed fewer microglia surrounding plaques, increased numbers of filamentous non-compacted plaques, and more p-tau-positive neurites around plaques (10).…”

Section: Resultsmentioning

confidence: 99%

Alzheimer's disease pathology in Nasu-Hakola disease brains

Satoh

Kino

Yanaizu

et al. 2018

IRDR

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“…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

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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.

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TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

Cited by 667 publications

References 49 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

Alzheimer's disease pathology in Nasu-Hakola disease brains

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

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