Two new papers from Christian Haass and colleagues at the German Center for Neurodegenerative Diseases (DZNE), Munich, underline the key role of the receptor TREM2 in mobilizing microglia to respond to injury. Microglia without the receptor remain locked in a homeostatic state, unable to clean up debris, the researchers report. Most of these data were previously discussed at the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29 to April 2 in Vienna (see Apr 2017 conference news). The findings are now published in the May 8 EMBO Reports and the May 30 EMBO Journal.

The EMBO Reports paper presents findings from TREM2 knockout mice. First author Fargol Mazaheri found that microglia from these mice migrated poorly toward diseased and damaged tissue, and were slow to extend processes. Gene expression analyses revealed that they made low levels of many proteins involved in chemotaxis and migration compared to wild-type cells. Some of these proteins, including CCL2, IL1b, TNF, and SPP1, are direct targets of TREM2 signaling. Overall, the expression profile of TREM2 knockout microglia resembled that of quiescent phagocytes, the authors note.

In the EMBO Journal, the researchers reported on mice that carry a TREM2 mutation, T66M. This variant prevents the receptor from reaching the cell surface, mimicking the effect of a knockout. T66M has been linked to frontotemporal dementia as well as Nasu-Hakola disease, which leads to bone lesions and white-matter defects in the brain that cause dementia (see Oct 2012 news). First author Gernot Kleinberger generated macrophages from bone marrow taken from T66M knock-in mice. These cells had trouble surviving and proliferating in vitro, and engulfed fewer bacteria and less fibrillar Aβ than wild-types. The authors also observed differences in the brain. As mice age, microglia normally become more active, but the T66M microglia remained dormant in year-old animals. This quiescence correlated with weaker cerebral blood flow and reduced brain glucose metabolism, suggesting an effect on overall brain health. People with Nasu-Hakola disease have poor brain blood flow and hypometabolism (see Ueki et al., 2000Klünemann et al., 2005Takeshita et al., 2005).—Madolyn Bowman Rogers


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News Citations

  1. New Evidence Confirms TREM2 Binds Aβ, Drives Protective Response
  2. Mutations in TREM2 Cause Frontotemporal Dementia

Paper Citations

  1. . Membranous lipodystrophy presenting with palilalia: a PET study of cerebral glucose metabolism. Acta Neurol Scand. 2000 Jul;102(1):60-4. PubMed.
  2. . The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005 May 10;64(9):1502-7. PubMed.
  3. . Regional cerebral blood flow in a patient with Nasu-Hakola disease. Ann Nucl Med. 2005 Jun;19(4):309-12. PubMed.

Further Reading

Primary Papers

  1. . TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 2017 Jul;18(7):1186-1198. Epub 2017 May 8 PubMed.
  2. . The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.