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. Author manuscript; available in PMC: 2022 Nov 26.
Published in final edited form as: Cell Calcium. 2022 Mar 26;104:102584. doi: 10.1016/j.ceca.2022.102584

TREM2 and calcium signaling in microglia – is it relevant for Alzheimer’s disease?

Evgenii Gerasimov 1, Ekaterina Pchitskaya 1, Ilya Bezprozvanny 1,2,*
PMCID: PMC9701094  NIHMSID: NIHMS1849547  PMID: 35366517

One of the most important functions of microglia in the brain is to release neurotrophic factors and cytokines in response to injury or irritation, causing changes in activity of the neighboring neurons [1]. Microglia express P2 purinoreceptors and are able to respond to glutamate, ATP, ADP and other nucleotides [2]. Microglia plays an important role in conditions of chronic stress, such as neuroinflammation in the brain resulting from neurodegenerative process, such as Alzheimer’s disease (AD). Some variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) are correlated with elevated risk for AD [3]. Polymorphisms in TREM2 were also identified in genetic studies of late onset AD (LOAD) [4]. Transcriptomic studies demonstrated microglia changes during progression of AD – gradual shift from homeostatic state to DAM (disease-associated microglia) state, which involves downregulation of homeostatic genes and the upregulation of genes associated with AD such as APOE and TREM2 [2]. These developments lead to search for potential AD therapeutic targets on microglia, such as TREM2, Toll-like receptors and Scavenger receptors [5].

A recent paper by Amit Jairaman at al [6] is focused on analysis of human induced pluripotent stem cell-derived microglia (iPSC-microglia). In this paper the authors investigated the purinergic signaling, cell motility and processes extension changes in TREM2 receptor knockout (KO) iPSC-microglia. The authors discovered that ADP induced calcium (Ca2+) release in normal iPSC-microglia while in KO cells response to ADP was supranormal and resulted in enhanced calcium Ca2+ responses (Fig 1). Another important difference was decrease in migration ability of TREM2 KO microglia in response to ADP. Similar changes were observed with mutations in TREM2 gene which were reported to result in a deficit in microglial chemotaxis and lowered response to neuronal injury [7]. Amit Jairaman at al further demonstrated that antagonists of purinergic receptors can rescue the migration deficit in TREM2 KO iPSC-microglia [6]. These results indirectly support an idea of blocking P2Y1 receptors as a target for AD treatment [8].

Figure 1. Abnormal calcium signaling in IPSC-microglia with TREM2 knockout.

Figure 1.

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Calcium responses to ADP stimulation in wild type (A) and TREM2 KO (B) microglia are compared. Levels of P2Y12 and P2Y13 receptors, InsP3-induced Ca2+ release and SOCE are elevated in TREM2 KO cells. Picture is crafted with the help of https://smart.servier.com/

Enhanced Ca2+ responses in TREM2 KO iPSC-microglia cells appear to be due to supranormal store operated calcium entry (SOCE) in these cells in response to ADP [6]. Previous studies demonstrated abnormal Ca2+ signaling and SOCE in neurons in variety of neurodegenerative models, including AD models [9]. However, Ca2+ signaling and SOCE abnormalities in microglia have not been previously studied in the context of AD, despite the importance of neuroinflammation for disease pathology. In a future it will be interesting to analyze Ca2+ signaling and chemotaxis in iPSC microglia from patients with familial AD mutations. It is also important to investigate potential connection between microglial Ca2+ signaling abnormalities, disturbed microglia motility and disease initiation and progression. Normalizing microglia behavior is considered to be one of the therapeutic strategies for AD treatment, but whether microglia activation in AD is beneficial or detrimental is still an open question. The study by Amit Jairaman at al [6] highlighted an importance of fine-tuning microglia sensitivity to stimulation during disease. These authors propose that Orai1 channel blockers may also be beneficial as they expected to normalize microglia function. However, Orai1 channels also play an important role in supporting neuronal SOCE [10], which may limit application of such an approach.

To summarize, the authors directly demonstrated important role of TREM2 in modulating purinergic and Ca2+ signaling and chemotaxis in iPSC-derived microglial cells. These findings have important implications for understanding basic biology of microglia and for targeting TREM2 and microglial signaling in the context of AD.

Acknowlegements.

The research in author’s laboratories is supported by the National Institutes of Health grant R01AG055577 (I.B.) and the Russian Science Foundation grant no. 21-74-00028 (E.P) I.B. holds the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research.

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