Because certain variants in TREM2 increase a person's risk of developing Alzheimer’s disease, how this microglial receptor influences AD pathology is an area of intense investigation. Now, researchers led by Zhentao Zhang, Renmin Hospital of Wuhan University, China, say the soluble ectodomain, sTREM2, tempers tau phosphorylation. In the October 21 Nature Communications, they reported that it binds transgelin-2 on the surface of neurons. This, they report, turns off the RhoA-ROCK-GSK3β kinase cascade inside the cells. GSK3β is a major tau kinase. The researchers propose that microglia ramp up sTREM2 secretion to protect neurons and that transgelin-2 is an sTREM2 receptor.
- Soluble TREM2 shed from microglia binds transgelin-2.
- GSK3β activity falls, reducing tau phosphorylation.
- Other scientists question where sTREM2 and transgelin-2 interact.
Other scientists are unconvinced. While some agreed that the sTREM2-transgelin-2 interaction reduced downstream tau pathology, others noted that transgelin-2 contains no transmembrane domain, hence cannot act as a cell-surface receptor. Further, Christian Haass of the German Center for Neurodegenerative Diseases in Munich thinks it is difficult to reconcile the study with TREM2 being a risk factor, since the AD-linked variant H157Y sheds the soluble domain prolifically, leaving less TREM2 on the cell surface to activate microglia. “According to these findings, this mutant should not be a risk variant, but rather a protective variant—how is that explained?” he asked (comment below).
Gary Landreth of the Indiana University School of Medicine, Indianapolis, recalled that TREM2 is no stranger to controversy. “The most prominent question posed about TREM2 is whether it elicits protective or detrimental actions, and the same observational data are used to argue both sides of this issue,” he wrote (comment below).
To explore sTREM2 function, co-first authors Xingyu Zhang and Li Tang added it to cultured neurons from P301S tau mice, which overexpress an FTD-causing mutant tau. Phosphorylation of tau fell at serines 202, 396, 404, and threonine 181. All four residues phosphorylated by GSK3β, hinting that sTREM2 silences the kinase.
The scientists suspected the RhoA-Rho-associated protein kinase (ROCK) cascade might be involved because it stimulates GSK3β and because chipping away at ROCK had been reported to reduce tau pathology in cultured human neurons (Feb 2016 news). When they added sTREM2 to SH-SY5Y neuroblastoma cells the ratio of inactive-to-active RhoA climbed, suggesting that the RhoA-ROCK-GSK3β pathway was silenced.
How might extracellular sTREM2 talk to RhoA within neurons? Zhang and Tang searched for receptors that might bind sTREM2. They isolated the protein and anything that stuck to it from the cell membrane fractions of SH-SY5Y cells using affinity purification, then analyzed the components by mass spectrometry. Among the 17 proteins that came along for the ride, one caught the researchers' eyes: transgelin-2 (TG-2). This 22kDa protein is expressed in most cell types but is particularly abundant in smooth muscle cells, where it binds actin to help it cross-link, hence the word “gel” in transgelin (reviewed by Yin et al., 2019). This was the only protein that bound sTREM2 that might fit the “receptor” category.
Others have plucked TG-2 from cell membranes, and one group claimed it acts as a receptor for metallothionein-2, linking this cysteine-rich protein to the relaxation of smooth muscle cells via inhibition of the RhoA-ROCK pathway (Yin et al., 2018).
Zhang and colleagues think sTREM2 similarly interacts with TG-2. They report finding sTREM2 bound to transgelin-2 in membrane fractions from wild-type and P301S neurons, and sTREM2 and TG-2 co-localized with neurons, microglia, and astrocytes in hippocampal tissue from P301S mice and from people who had had AD.
TSG12, a small molecule that emerged from a prior screen of TG-2-binding compounds, not only relaxes smooth muscle cells, but Zhang and colleagues found it also quieted GSK3β activity and prevented phosphorylation of tau serines 202 and 396 in neurons from P301S mice. This led the authors to conclude that transgelin-2 acts as a receptor for sTREM2 (image below).
Others are doubtful, partly because TG-2 contains no transmembrane domain. “We cannot exclude that it’s membrane-associated, but it’s not membrane-spanning,” Kai Schlepckow, Ludwig Maximilians University, Munich, told Alzforum. Schlepckow accepts that transgelin-2 might mediate effects of sTREM2, but does not think it does so through direct binding at the neuron surface. He believes neuronal receptors for sTREM2 are still to be found.
Michael Willem, also from LMU, agreed with his colleague. He pointed out that neurons express little transgelin-2 compared to other cells, such as smooth muscles. “Much more work needs to be done to uncover a specific sTREM2 receptor selectively expressed by neurons to explain the observed changes [in tau phosphorylation],” he wrote (comment below).
Zhang and Tang report that overexpressing sTREM2 in the hippocampi of P301S mice tempered GSK3β’s activity, lowered p-tau, and preserved synapses (image below). This translated to better memory, since the mice found a hidden platform in a water maze faster than P301S controls, and spent more time exploring the new arm of a Y-maze. These effects ceased when the researchers knocked down transgelin-2 in the hippocampus.
More sTREM2, Less p-Tau. P301S mice (left) have higher phospho-tau levels in the hippocampus than mice overexpressing both P301S and sTREM2 (right). [Courtesy of Zhang et al., Nature Communications, 2023.]
The scientists mimicked the protective effects with a brain-permeable, 13-amino-acid fragment of sTREM2. When they injected it every five days into the abdomens of P301S mice beginning when they were 3 months old, the mice had made half as much hippocampal p-tau, sprouted more synapses, and performed better on the water maze test than did untreated controls. “While Zhang et al. do not address how microglia in the AD brain […] increase the production of sTREM2 and the inhibition of the Rho-ROCK-GSK-3β pathway to prevent tau hyperphosphorylation, they have identified residues 77-89 of sTREM2 as a potential therapeutic peptide to achieve this goal,” wrote Khalid Iqbal of the New York State Institute for Basic Research in Staten Island (comment below).—Chelsea Weidman Burke
Mutation Interactive Images Citations
Research Models Citations
- Yin LM, Ulloa L, Yang YQ. Transgelin-2: Biochemical and Clinical Implications in Cancer and Asthma. Trends Biochem Sci. 2019 Oct;44(10):885-896. Epub 2019 Jun 27 PubMed.
- Yin LM, Xu YD, Peng LL, Duan TT, Liu JY, Xu Z, Wang WQ, Guan N, Han XJ, Li HY, Pang Y, Wang Y, Chen Z, Zhu W, Deng L, Wu YL, Ge GB, Huang S, Ulloa L, Yang YQ. Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance. Sci Transl Med. 2018 Feb 7;10(427) PubMed.
- Zhang X, Tang L, Yang J, Meng L, Chen J, Zhou L, Wang J, Xiong M, Zhang Z. Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease. Nat Commun. 2023 Oct 21;14(1):6670. PubMed.