Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease

Jay, Taylor R.; Hirsch, Anna; Broihier, Margaret L.; Miller, Crystal; Neilson, Lee E.; Ransohoff, Richard M.; Lamb, Bruce T.; Landreth, Gary E.

doi:10.1523/jneurosci.2110-16.2017

Cited by 94 publications

(133 citation statements)

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“…Reduced TREM2 gene dosage was found to enhance amyloid pathology in one of the studies [78], while it decreased amyloid pathology in another study [7]. Importantly, the latter group recently showed that TREM2 deficiency in APP/PS1 mice lead to reduced amyloid burden at an early disease stage, while it enhanced amyloid burden at a late disease stage [79]. When AD pathogenesis is investigated in transgenic mouse models, human ApoE isoforms are often expressed, either by using a heterologous promoter [80] or by gene replacement in animals devoid of murine ApoE [81].…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

Jendresen

Årskog

Daws

et al. 2017

J Neuroinflammation

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BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer’s disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE.MethodsTo investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible β-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3ζ intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE.ResultsApoE was found to be an agonist to human TREM2 with EC50 in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms ε2, ε3, and ε4 bound to human TREM2 with K d in the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130–149).ConclusionsAn ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer’s disease is discussed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0835-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

Jendresen

Årskog

Daws

et al. 2017

J Neuroinflammation

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“…While there have been mixed results on the accumulation of Aβ, all Trem2 −/− studies have shown decreased clustering of myeloid or microglial cells around plaques, suggesting a defect in microgliosis, or microglia activation [30, 31, 42, 43, 45, 47]. These studies have also found that Trem2 −/− mice have fewer microglia and increased microglia apoptosis.…”

Section: Trem2 In Diseasementioning

confidence: 96%

“…Although there have been reports of TREM2 detection on non-myeloid/microglial cells in the CNS [4, 36], these cases have largely used immunostaining methods to identify neuronal expression of TREM2, which may identify sTREM2 produced by microglia that is released and bound to neurons which express a TREM2 ligand [26, 37–39]. RNA expression analyses have confirmed Trem2 is expressed selectively on microglia in the brain [40, 41], and parabiosis experiments show these microglia are most likely resident microglia and not infiltrating monocytes [42], although this is still controversial [43]. Within human AD brain, laser microdissection showed Trem2 is highly expressed on plaque-associated microglia [44], and high resolution microscopy techniques showed that TREM2 protein is concentrated on microglia processes that are in contact with amyloid beta (Aβ) plaques [45].…”

Section: Trem2 In Diseasementioning

confidence: 99%

“…However, the Aβ phenotypes have been inconsistent in these studies. Some studies using Trem2 − / − mice found no change in the overall plaque load [42, 47], while further studies found increased [30, 43] or even decreased burden [31, 43]. Some of these differences are perhaps explained by the timing of data collection [43], although they could suggest Aβ clearance is not the only role for TREM2.…”

Section: Trem2 In Diseasementioning

confidence: 99%

“…TREM2 deficiency is reported to have opposing effects on Aβ levels and disease pathology during early and late disease [43]. …”

Section: Trem2 Function and Model For Ligand Engagementmentioning

confidence: 99%

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TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

177

166

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The protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer’s disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases, recent advances in our understanding of TREM2, and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease-risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.

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Alzheimer's genetic risk factor FERMT2 (kindlin‐2) controls axonal growth and synaptic plasticity in an APP‐dependent manner

Eysert

CoulonVreulx

Flaig

et al. 2020

Alzheimer's & Dementia

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Background Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome‐wide high‐content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. Method We combined genome‐wide high‐content screenings to identify miRNAs (n = 2,555) and target genes (n = 18,107) involved in the APP metabolism. To predict the function(s) of miRNAs that target these genes, pathway enrichment analysis was performed using DIANA Tools mirPath (v3.0). CRISPR/Cas9 technology has been used to generate HEK293 cell lines carrying rs7143400 variant located in the FERMT2 3’UTR and its impact on miRNA binding. Involvement of FERMT2 in axonal growth and synaptic connectivity was assessed using primary neurons cultured in microfluidic devices that fluidically isolate axons from their cell bodies. The functional impact of FERMT2 on CA1 basal synaptic transmission and long‐term potentiation (LTP) has been recorded in ex vivo mouse hippocampal slices, after stereotactic lentivirus injection allowing expression of shNT, shFERMT2 or shAPP. Result Our systematic approaches led us to characterize 180 genes targeted by 41 miRNAs as modulators of APP metabolism. Among these genes, we focused on FERMT2, a known genetic risk factor of sporadic AD. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under‐expression impacts axonal growth, synaptic connectivity and long‐term potentiation in an APP‐dependent manner.Lastly, the rs7143400‐T allele, which is associated with an increased AD risk and localized within the 3’UTR of FERMT2, induced a down‐regulation of FERMT2 expression through binding of miR‐4504. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Conclusion Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under‐expression in neurons and insight on how this may influence AD pathogenesis.

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Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease

Cited by 94 publications

References 1 publication

The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

TREM2-Ligand Interactions in Health and Disease

Alzheimer's genetic risk factor FERMT2 (kindlin‐2) controls axonal growth and synaptic plasticity in an APP‐dependent manner

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