Weill Cornell Medicine Events

Microglial Modulation in Alzheimer’s diseases – Innovative Therapies or Devilish Gambling?"

Christian Haass, PhD

Professor of Biochemistry

German Center for Neurodegenerative Diseases (DZNE) 

Munich Cluster for Systems Neurology (SyNergy),

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München

 

Abstract

Alzheimer’s disease (AD) is currently untreatable, and therapeutic strategies aimed to slow cognitive decline have not yet been successful. Many of these approaches have targeted the amyloid cascade, indicating that additional treatment strategies are required. Recent genome wide association studies have identified a number of risk factors in genes expressed in microglia, including the Triggering receptor expressed on myeloid cells 2 (TREM2).  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 biomarker studies revealed that TREM2 may protect humans from AD, thus increasing TREM2 activity may be a new therapeutic option for AD. Since we found that TREM2 signaling is terminated via proteolytic shedding of the TREM2 ectodomain, we sought to enhance TREM2 activity, by selectively inhibiting access of ADAM10/17 to TREM2.  We generated a panel of monoclonal antibodies against the stalk region of TREM2, which encompasses the cleavage site, with the aim to compete for ADAM mediated shedding. Monoclonal antibody 4D9, which binds to an epitope close to the ADAM10/17 cleavage site, stabilized TREM2 on the cell surface, reduced its shedding and concomitantly activated phospho-SYK signaling in a dose dependent manner. Moreover, 4D9 stimulated survival of cultured macrophages, increased myelin debris uptake of primary microglia and reduced the amyloid burden in a mouse model for AD pathology.  Thus, 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 may play a protective role.

 

Publicaitons

 

  • 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

https://doi.org/10.1016/j.neuron.2020.09.029

Dial-In Information

Contact Sophy Aguilar: sot2002@med.cornell.edu for Zoom details.

Thursday, December 16, 2021 at 12:00pm to 1:00pm

Virtual Event
Event Type

Lecture/Seminar

Departments

Brain and Mind Research Institute

Mission

Research

Photo Alt Text

PINS 12/16

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