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Séminaire - Oleg ButovskyDysregulation of the APOE-TGFB pathway leads to loss of the microglial homeostatic signature in neurologic diseases

Abstract :

Microglia are resident macrophages of the central nervous system (CNS) that participate both in normal CNS function and disease. We identified a unique molecular and functional homeostatic signature in microglia. Based on this signature, we generated novel microglial surface specific antibodies and identified novel targets in resident microglia that can serve as therapeutic targets. We also identified unique patterns of microglia dysfunction associated with CNS disease in animal models of EAE, ALS and AD. We found that the homeostatic microglial signature is dependent on TGFβ signaling. In mouse models of MS ALS and AD microglia acquire a cytotoxic phenotype mediated by intrinsic activation of the APOE pathway which suppresses the microglia homeostatic molecular properties and leads to uncontrolled chronic inflammation. Treatments aimed at targeting microglia by suppressing the APOE pathway results in activation of both the TGFβ pathway and TAM system (Tyro3, Axl and Mertk) which abrogates the inflammatory microglial phenotype and restores microglial homeostatic  properties. In summary, we have identified the APOE-TGFβ axis as a critical common regulatory pathway in microglia. This pathway is dysregulated in both inflammatory and degenerative diseases of the CNS.  

Selected publications

Butovsky, O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, and Schwartz M. From the Cover: Glatiramer acetate fights against Alzheimer's Disease by inducing dendritic-like microglia expressing insulin- like growth factor 1. Proc Natl Acad Sci U S A. 2006 103:11784-11789.

Schwartz M, Butovsky O, Kipnis J. Does inflammation in an autoimmune disease differ from inflammation in neurodegenerative diseases? Possible implications for therapy. J Neuroimmune Pharmacol. 2006 Mar;1:4- 10. Review.

Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci. 2007 26:413-416

Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M. Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol Cell Neurosci. 2007 35:490-500 (Invited review).

Butovsky O, Gabriely G, Lanser A, Dake B, Gopal M, Doykan C, Wu P, Reddy G, Iyer L, Lawson R, Berry J, Cudkowicz M, Weiner H. Modulation of inflammatory monocytes with a unique microRNA-gene signature ameliorates ALS in a mouse model. J. Clin. Invest. 2012 122:3063-3087. PMCID: PMC3428086.

Butovsky O, Jedrychowski M, Moore C, Cialic R, Lanser A, Gabriely G, Koeglsperger T, Dake B, Wu P, Doykan C, Fanek Z, Liu L, Chen Z, Rothstein J, Ransohoff R, Gygi S, Antel J, Weiner H. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014 17:131-143. PMCID: PMC4066672.

Scientific focus :

My major scientific interest is to understand the biology of resident microglia and peripheral inflammatory monocytes in homeostasis and neurodegenerative conditions. During my Ph.D. studies at the Weizmann Institute of Science, I studied the role of microglial cells in regulating the Ab plaque deposition in AD models, identified subpopulations of microglia and demonstrated how microglia can be both beneficial or detrimental in the context of neurodegeneration. My recently published work has identified a unique microglial signature in both mice and humans and is elucidating the relationship of microglia to CNS disease including AD, MS and ALS. With the new knowledge gained, I hope to address fundamental questions of microglial biology in animal models of CNS diseases and apply this knowledge towards the development novel microglia-targeting therapies.