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Microglial function and dysfunction of TREM2 and ABI3, two major risk factors for late onset Alzheimer’s disease

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Genome wide association studies have identified a number of risk factors for late onset Alzheimer’s disease (LOAD) in genes expressed in microglia, among them the Triggering receptor expressed on myeloid cells 2 (TREM2) and Abl interactor family member 3 (ABI3). TREM2 is essential for the transition of homeostatic microglia to disease associated microglia. TREM2 loss of function locks microglia in a homeostatic state, and affects a multitude of microglia functions such as chemotaxis, phagocytosis, cell survival, lipid- and energy metabolism. Our most recent longitudinal biomarker studies in DIAN revealed that higher TREM2 levels during the pre-clinical phase may protect humans from cognitive decline and brain shrinkage. Thus increasing TREM2 activity may be a new therapeutic option for AD. We developed TREM2 modulating strategies by generating antibodies, which boost TREM2 protective functions. Our findings demonstrate that antibodies elevating full-length TREM2 on the cell surface allow selective modulation of TREM2 dependent functions in microglia and macrophages, which may be of potential therapeutic benefit in a variety of disorders where TREM2 plays a protective role. Since antibody mediated microglial overactivation is a concern for the application of such antibodies, we investgated the protective/detrimental function of hyperactivated microglia in models for GRN deficiency. Surprisingly, we found that inhibition of hyperactivation by reducing TREM2 signaling even further increased neurodegeneration in GRN knockout mice. Thus even hyperactivated microglia retain at least some protective activity. Moreover, these findings also demonstrated that microglial activation is reversible, further supporting the highly dynamic nature of microglia. ABI3 is involved in the coordinated remodeling of the actin cytoskeleton via F-actin nucleation, which is a major regulator of cell shape, cytokinesis, membrane internalization, and chemotaxis. To generate a model that closely mimics the ABI3 mutations found in LOAD , we introduced the heterozygous mutation into the corresponding position within the mouse genome (S212F) and crossed these animals to a mouse model of amyloidogenesis. In patient derived microglia as well as microglia from our mouse model, mutant ABI3 fails to undergo phosphorylation at and around the site of the serine to phenylalanine exchange. Consistent with a central role of ABI3 in F-actin nucleation, failure of phosphorylation alters microglial morphology by reducing their volume and branch points. I will demonstrate an unexpected dysequilibrium between microglia mediated plaque compaction and vascular, Abeta mediated damage in ABI mutant heterozygous mice.

Further reading: Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang CC, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C (2020) Enhancing Protective Microglial Activities With a Dual Function TREM2 Antibody to the Stalk Region. EMBO Mol Med, 12(4): e11227.

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 (2019) 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.

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.

Review article: Lewcock JW, Schlepckow K, Di Paolo G, Tahirovic S, Monroe KM, Haass C (2020) Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease. Neuron

This talk is part of the Microglia webinar series series.

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