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Function and dysfunction of microglia in neurodegenerative disorders

CMCB Green Seminar

Date:14.03.2019, 16:00 - 17:00
Speaker: Prof. Christian Haass, Ludwig-Maximilians-University & German Center for Neurodegenerative Diseases (DZNE), Munich
Location: CRTD, auditorium
Host: Prof. Gerd Kempermann

We demonstrate that amyloid plaque seeding is increased in the absence of functional TREM2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque associated Apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed a microglial origin of plaque associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in TREM2 loss of function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional TREM2 early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque associated ApoE.

The 5 most important publications
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, Sebastian Monasor L, Tahirovic S, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Jucker M, Holtzman DM, Meyer-Luehmann M, Haass C. Loss of TREM2 function increases amyloid seeding but reduces plaque associated ApoE. Nature Neuroscience, 22(2): 191-204.

Suárez-Calvet M, Caballero MA, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C for the Dominantly Inherited Alzheimer Network (2016) Early changes of CSF sTREM2 in Dominantly Inherited Alzheimer's Disease follow markers of Amyloid Deposition and Neuronal Injury. Science Translational Medicine 8(369): 369ra178.

Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A, Hampel H, Muller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Muller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C (2015) eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526 :443-7.

Kleinberger G., Yamanishi Y., Suárez-Calvet M., Czirr E., Lohmann E., Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F., Tahirovic S., Lleó A., Alcolea D., Fortea J., Willem M., Lammich S., Molinuevo J. L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M., Sleegers K., van der Zee J., Martin J.-J., Engelborghs S., Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H., Wyss-Coray T., Hardy J., Colonna M. & Haass C. (2014) TREM2 mutations linked to neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine, 6, 1-29.

Willem, M., Garratt, A.N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C. and Haass, C. (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664-6.

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