Abstract
Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD.
Highlights
It is still important to verify that Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) and/or soluble TREM2 (sTREM2) are protective
Some of evidence indicating that sTREM2 is protective against Alzheimer’s disease (AD), may alternatively be interpreted as full-length TREM2 is protective
There is a need for experiments that distinguish between these possibilities, or directly show that sTREM2 is protective
Summary
Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor found on the plasma membrane of myeloid cells. Injection of sTREM2 into the brains of mice expressing the amyloid precursor protein (APP) induced activation and proliferation of microglia, plus increased expression of pro-inflammatory cytokines, and increased microglial phagocytosis of Aβ (Zhong et al, 2019). TREM2 knockout mice, crossed with APP-expressing mice, have more fibrous and less compact plaques (Condello et al, 2015; Wang et al, 2016; Yuan et al, 2016; Song et al, 2018), and while this has been attributed to less microglial phagocytosis of the plaques because of less full-length TREM2, the result might alternatively be due to sTREM2 blocking Aβ aggregation and/or sTREM2 activating microglia to phagocytose plaques. Humans (and mice) with heterozygous R47H TREM2 have more fibrous plaques with more neuritic pathology (Yuan et al, 2016), which again might be explained by either R47H sTREM2 promoting Aβ fibrillation, or by reduced microglial phagocytosis of plaques
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