Ever since the R47H partial-loss-of-function variant of the microglial receptor TREM2 was found to increase risk for Alzheimer’s disease, scientists have wondered if boosting TREM2 signaling would be protective. Alas, exploiting this receptor for therapeutic purposes may not be so easy. In the June 17 Journal of Clinical Investigation, researchers led by David Holtzman at Washington University, St. Louis, report that, surprisingly, R47H TREM2 protects against neurodegeneration in a mouse model of tauopathy. It appears that the very same variant that exacerbates amyloidosis in one model, attenuates the toxicity associated with neurofibrillary tangles in another.
- The R47H variant of TREM2 increases risk for AD.
- In a mouse model of tauopathy, it protects against neurodegeneration.
- Therapeutically targeting TREM2 may not be simple.
“This strongly implies that, for any therapeutic approach that targets TREM2 function, one needs to define a precise therapeutic window, which may be quite narrow,” Christian Haass, Ludwig-Maximilians University, Munich, wrote to Alzforum. He was not involved in the work, but has developed antibodies to activate TREM2 signaling that are now in preclinical development.
In recent years, consensus has grown that the R47H mutation reduces TREM2 signaling in, and proliferation of, microglia, allowing amyloid plaque formation to run amok (May 2016 news; Jay et al., 2015; Ulrich et al., 2014; Cheng-Hathaway et al., 2018). Its effect on tau pathology has turned out to be slightly different.
Three years ago, Holtzman’s group knocked out TREM2 in PS19 mice that expressed the P301S mutant form of human tau. Lo and behold, complete loss of TREM2 protected this strain from neurodegeneration (Leyns et al., 2017). Around the same time, researchers at Bruce Lamb’s lab at the Indiana University School of Medicine, Indianapolis, reported that TREM2 KO exacerbated tau neuropathology in a weaker tauopathy model, suggesting disease stage might be important for TREM2 responses (Bemiller et al., 2017). Li Gan and colleagues also found that while complete TREM2 knockout prevented microglial activation and hippocampal atrophy, haploinsufficiency made them worse and exacerbated tau pathology (Sayed et al., 2018). What would happen if the TREM2 activity was merely toned down, as in people who carry the R47H variant?
First author Maud Gratuze crossed PS19 mice lacking endogenous TREM2 with mice expressing human TREM2 containing either the common arginine at amino acid 47, or the histidine risk variant. Then she looked for effects on tau pathology in each. At 3 months, the R47H TREM2 mice had less phosphorylated tau in the hippocampus than did mice expressing the common TREM2 variant. By 9 months, this difference extended to the piriform cortex. Also at 9 months, atrophy was milder by a quarter in the hippocampus and by a third in the cortex in the R47H mice. Enlargement of brain ventricles, which usually occurs as brain tissue atrophies, was reduced by two-thirds, as well (see image above).
What gives? Looking at microglia, Gratuze found that they were more quiescent than in the R47H mice. Iba1, a marker of activation, was down a third and expression of disease-associated (DAM) microglial genes was lower, as well. The phagolysosomal marker CD68 also indicated less microglial activity in the R47H mice.
All this seems to amount to protection of synapses in the context of tauopathy. Expression of complement C1q, an “eat me” signal for synapses, was 60 percent lower in the R47H mice compared with those expressing the common TREM2 variant. SEQUIN, a new method for counting synapses en masse, showed more of them in the R47H mice (Jun 2020 news).
All told, the data suggest that the R47H mutation protects neurons by toning down microglial responses and leaving synapses intact. Gratuze found that this might be true in people, as well, even though this sounds counterintuitive on the face of it, given that R47H is associated with higher risk of getting AD. She found much less co-localization of the synaptic marker PSD95 with the CD68 phagolysosomal marker in postmortem tissue from AD patients carrying the R47H variant (see image at right).
Holtzman believes the R47H variant is protective in this tauopathy model. What could that mean in the context of Alzheimer’s, when amyloid plaques are part of the pathology? “It suggests that R47H would get more dystrophic neurites around amyloid plaques as well as more tau seeding and spreading during the preclinical and early clinical phase of disease,” Holtzman wrote to Alzforum. “This would translate into R47H carriers being more likely to ‘develop’ symptomatic AD, which is what the clinical and genetic data show, but once tauopathy becomes significant, that clinical disease progression might be slower in humans with R47H.”
Where does that leave people who don’t carry the risk variant? “At the simplest level, given the increased risk associated with R47H, we might want to increase function of TREM2, but that would only make sense during the preclinical phase,” Holtzman said. He believes we have to be very careful about when to treat, and whether to agonize or antagonize TREM2. “I think we need to understand a little more about tweaking TREM2 function up or down in different ways in different models that mimic different stages of disease, and of course in Phase 1/2 human studies, to see in which direction biomarkers go and to see how these mouse studies are relevant in people.” He also cautioned that patients would have to be monitored more regularly to see if they were getting better or worse.—Tom Fagan
- Barrier Function: TREM2 Helps Microglia to Compact Amyloid Plaques
- Shiny SEQUIN: New Technique Counts Synapses Over Large Brain Volumes
Research Models Citations
- Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015 Mar 9;212(3):287-95. Epub 2015 Mar 2 PubMed.
- Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, Stewart FR, Piccio L, Colonna M, Holtzman DM. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014 Jun 3;9:20. PubMed.
- Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, von Saucken VE, Williams RY, Karlo JC, Moutinho M, Xu G, Ransohoff RM, Lamb BT, Landreth GE. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018 Jun 1;13(1):29. PubMed.
- Leyns CE, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.
- Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, Kokiko-Cochran ON, Crish SD, Lasagna-Reeves CA, Ransohoff RM, Landreth GE, Lamb BT. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener. 2017 Oct 16;12(1):74. PubMed.
- Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D, Hauduc A, Ludwig C, Gao F, Clelland C, Zhan L, Cooper YA, Davalos D, Akassoglou K, Coppola G, Gan L. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10172-10177. Epub 2018 Sep 19 PubMed.
No Available Further Reading
- Gratuze M, Leyns CE, Sauerbeck AD, St-Pierre MK, Xiong M, Kim N, Serrano JR, Tremblay MÈ, Kummer TT, Colonna M, Ulrich JD, Holtzman DM. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J Clin Invest. 2020 Sep 1;130(9):4954-4968. PubMed.