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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.
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Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
This paper suggests a dual role of TREM2 during disease evolution. Early on TREM2 risk variants increase Aβ toxicity and promote its spreading (see also Parhizkar et al., 2019). Similarly, TREM2 risk variants appear to promote tau spreading in early phases of the disease. Later in diseases, at least in pure tauopathies, opposite consequences of reduced TREM2 function are observed, which probably are due to reduced synaptic pruning by malfunctioning microglia. 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.
However, this paper also raises additional questions. In AD brains from TREM2 carriers, significantly less synaptic pruning was observed (i.e., less PSD 95 positive puncta in CD68-positive vesicles of microglia). What happens under these circumstances to tau pathology? Is there less tau phosphorylation, at least late in AD? Furthermore, synaptic pruning may also be protective as long as weak or malfunctioning synapses are removed. Is memory improved in PS19 mice upon expression of an AD-associated TREM2 risk variant?
Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019 Feb;22(2):191-204. Epub 2019 Jan 7 PubMed.View all comments by Christian Haass
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