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TREM2 — a key player in microglial biology and Alzheimer disease

Abstract

Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.

Key points

  • During the development of Alzheimer disease (AD)-associated pathology, homeostatic microglia progressively acquire a unique transcriptional and functional signature and evolve into disease-associated microglia (DAM).

  • DAM can contain amyloid-β plaques and protect surrounding neuronal tissue.

  • Rare loss-of-function variants in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing AD in humans.

  • Microglia require TREM2 for full acquisition of a DAM profile.

  • TREM2 is needed to enhance mechanistic target of rapamycin (mTOR) signalling and to boost the metabolic capacity of microglia.

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Fig. 1: Domain structures of TREM2 and associated signalling adaptor molecules DAP12 and DAP10.
Fig. 2: Generation of soluble TREM2 by sequential actions of ADAM17, ADAM10 and γ-secretase.
Fig. 3: Signalling pathways linking TREM2 activation and energetic cellular metabolism.
Fig. 4: The TREM2–mTOR axis potentiates and sustains the microglial response to amyloid-β plaques.

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Acknowledgements

Review criteria

This Review serves as an overview of the current state of the field regarding triggering receptor expressed on myeloid cells 2 (TREM2) in Alzheimer disease (AD) pathogenesis, including the presentation of conflicting data. The authors primarily used PubMed to search the literature, focusing predominantly on the period between 2013, when TREM2 variants associated with an increased risk of AD were first reported, and the final submission date in February 2018. Supporting studies published before 2013 regarding AD and TREM2 were also reviewed. Search terms included “TREM2”, “TREM2 and Alzheimer’s disease”, “TREM2 and microglia”, “TREM2 and macrophages”, “Alzheimer’s disease” and “TREM2 and neurodegeneration”.

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Correspondence to Marco Colonna.

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Ulland, T.K., Colonna, M. TREM2 — a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14, 667–675 (2018). https://doi.org/10.1038/s41582-018-0072-1

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