Certain mutations in TREM2 strongly increase risk for late-onset Alzheimer’s. Could tweaking the function of this microglial receptor help people with the disease? A new study suggests as much. In the August 28 Science Translational Medicine, researchers led by Christian Haass at the German Center for Neurodegenerative Diseases in Munich report that people with Alzheimer’s pathology who had more of a soluble TREM2 fragment in their cerebrospinal fluid declined more slowly on memory tests than did those with less sTREM2. Haass had reported preliminary data at the 2019 AD/PD conference in Lisbon, Portugal (Apr 2019 conference news). “Activating TREM2-dependent microglial functions could be a protective therapeutic approach,” Haass told Alzforum.
- In AD, higher CSF sTREM2 correlates with slower cognitive decline.
- This holds true regardless of disease stage.
- Does this mean activating TREM2 may be beneficial?
Most pathological TREM2 variants disrupt the protein’s function (Apr 2017 conference news; Jan 2018 news). Since the receptor supports the health of microglia and their responses to amyloid and other brain insults, researchers believe loss of TREM2 function bodes ill for the brain (Aug 2017 news; Sep 2017 news; Mar 2018 news). Nonetheless, depending on disease stage and pathology, some studies have delineated harmful roles for TREM2 (Jul 2018 conference news).
To better understand the role of TREM2 in disease, Haass and colleagues turned to the Alzheimer’s Disease Neuroimaging Initiative. Joint first authors Michael Ewers, Nicolai Franzmeier, and Marc Suárez-Calvet analyzed data from 385 participants, average age 73. One hundred of them were cognitively normal and free of AD pathology, as judged by CSF levels of Aβ42 and p181-tau. The remaining 285 tested positive for amyloid and p-tau. In this latter group, 35 were cognitively healthy, 184 had mild cognitive impairment, and 66 had dementia. All underwent lumbar puncture at baseline and subsequently took repeated cognitive tests over an average of four years.
As expected from previous studies, baseline CSF sTREM2 was higher in people with AD pathology than in cognitively and biomarker-normal controls. But was the sTREM2 helpful or harmful? To find out, the researchers controlled for not just the known confounders of age, sex, and education, but also for clinical status and CSF Aβ42 and p181-tau. That way, they could compare people at the same disease stage and level of pathology. Their analysis showed that in people with comparable disease, higher baseline sTREM2 associated with slower decline over several years on an episodic memory composite, the ADNI-MEM. When the researchers used the sTREM2/p181-tau ratio, higher baseline numbers correlated with slower decline on both the ADNI-MEM and the ADAS13, a measure of global cognition.
The findings held in both the MCI and dementia subgroups. A Cohen’s d analysis, which measures how one variable affects another, calculated that CSF sTREM2 buoyed the ADNI-MEM score with an effect size of 0.43. This was similar to the effect of p181-tau on cognition—0.47. These are considered small to medium effect sizes. A person’s baseline CSF sTREM2/p181-tau ratio also associated with slower progression from cognitively healthy to MCI and from MCI to AD.
In addition to the cognitive protection, the researchers found hints of a link between sTREM2 and hippocampal preservation. Among 184 participants with CSF AD pathology who had undergone longitudinal MRI imaging, high baseline sTREM2 or high sTREM2/p181-tau was linked with slower hippocampal atrophy, although the results missed statistical significance. A previous cross-sectional study by Haass and colleagues at DZNE and at the Barcelonaβeta Brain Research Center in Spain had correlated high CSF sTREM2 with more gray matter in several cortical regions affected by AD, including temporal and precuneus. This was seen in 27 people with MCI, but not in AD (Gispert et al., 2016). However, it was unclear if the greater volume represented preserved gray matter, or swelling due to inflammation (Aug 2016 conference news).
“These data argue that sTREM2 has salutary actions on disease pathogenesis,” Gary Landreth at Indiana University School of Medicine in Indianapolis wrote to Alzforum (full comment below). A recent mouse study supports this conclusion, reporting that sTREM2 injected into 5xFAD mouse brain activated microglia to clean up plaques (Apr 2019 news).
Does this mean that activating TREM2 on the microglial cell surface would help the brain? Haass thinks yes. Because sTREM2 is cleaved from the full-length protein at the cell surface, he believes it likely reflects microglial TREM2 signaling. However, others question this. Landreth pointed to research claiming that up to a quarter of sTREM2 arises from alternative splicing, suggesting it may not correlate with TREM2 signaling (Del-Aguila et al., 2019). Even sTREM2 generated by shedding might oppose signaling if it lowers the amount of intact receptor available on the cell surface, he wrote. David Hansen at Genentech in South San Francisco suggested that sTREM2 shedding could be a protective mechanism that lowers harmful microglial signaling through full-lengthTREM2. In that case, activating TREM2 would be counterproductive for AD patients. Or, sTREM2 might have nothing to do with signaling, and could simply be a marker for microglial abundance. “Relating CSF sTREM2 measurements with additional biomarkers of microglial abundance and active TREM2 signaling will help resolve these uncertainties,” Hansen wrote to Alzforum (full comment below).
Many pharmaceutical companies are developing TREM2 activators. However, Haass cautioned that too much microglial activity can be as bad as too little. His lab recently reported that in progranulin-knockout mice, hyperactive microglia hasten neurodegeneration (Apr 2019 conference news). He believes more basic research is needed before taking TREM2 activators to trials. “We should be very cautious, because nobody knows if microglial activation is reversible,” Haass said. Several groups, including Haass’ lab, have developed TREM2 antibodies, with at least one already in Phase 1 (May 2019 conference news).
Given that the relationship between sTREM2 and TREM2 signaling remains murky, future trials will need better readouts for the latter, Haass believes. He suggested that changes in microglial lipid metabolism might make a more direct marker for TREM2 activation than CSF sTREM2. TREM2 senses extracellular lipids such as myelin debris and cholesterol. Microglia expressing pathologic mutants of the receptor cannot properly take up or process them, according to research from Denali Therapeutics in South San Francisco (Apr 2019 conference news). This suggests that buildup of lipids such as cholesterol esters could be a marker of poor TREM2 function. In collaboration with Denali, Haass is developing a lipid readout for TREM2 activity.—Madolyn Bowman Rogers
Mutation Interactive Images Citations
- Parsing How Alzheimer’s Genetic Risk Works Through Microglia
- New Evidence Confirms TREM2 Binds Aβ, Drives Protective Response
- New Mouse Models Reveal Unexpected Property of TREM2
- Without TREM2, Microglia Run Out of Gas
- ApoE and Trem2 Flip a Microglial Switch in Neurodegenerative Disease
- TREM2 Binds Aβ, Reprograms Microglia to Curb Plaques
- TREM2: Diehard Microglial Supporter, Consequences Be DAMed
- Refining Models of Amyloid Accumulation in Alzheimer’s Disease
- Cut Loose, Soluble TREM2 Beckons Microglia to Mop Up Plaques
- Antibodies Against Microglial Receptors TREM2 and CD33 Head to Trials
- Could Greasing the Wheels of Lipid Processing Treat Alzheimer’s?
Research Models Citations
- Gispert JD, Suárez-Calvet M, Monté GC, Tucholka A, Falcon C, Rojas S, Rami L, Sánchez-Valle R, Lladó A, Kleinberger G, Haass C, Molinuevo JL. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease. Alzheimers Dement. 2016 Dec;12(12):1259-1272. Epub 2016 Jul 14 PubMed.
- Del-Aguila JL, Benitez BA, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, Farias FH, Fernández MV, Ibanez L, Jiang S, Perrin RJ, Cairns NJ, Morris JC, Harari O, Cruchaga C. TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers. Mol Neurodegener. 2019 May 8;14(1):18. PubMed.
- Paper Alert: TREM2 Crucial for Microglial Activation
- MS4A Alzheimer’s Risk Gene Linked to TREM2 Signaling
- Without TREM2, Plaques Grow Fast in Mice, Have Less ApoE
- Gently Used: Can Recycled Microglia Receptors Prevent Plaque?
- TREM2, Microglia Dampen Dangerous Liaisons Between Aβ and Tau
- Paper Alert: MS4A Variants May Sway Alzheimer’s Risk Via TREM2
- ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome
- Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.