26th Meeting of the Hellenic Society for Neuroscience, November 29-December 1, 2013 Jointly with FP7 REGPOT NEUROSIGN
PLENARY LECTURE III: MICROGLIAL DISEASES
CLEARANCE
FUNCTION
IN
NEURODEGENERATIVE
Linnartz-Gerlach B., Bodea L.G, Claude J., Neumann H. Institute of Reconstructive Neurobiology, University Hospital of Bonn, University of Bonn, Germany. Microglia express innate immune receptors for the recognition of intact or lesioned cells of the central nervous system. Lesioned and/or complement opsonized cells are recognized by the triggering receptor expressed on myeloid cells-2 (TREM2) and the complement receptor-3. Both receptors signal via the transmembrane adaptor protein DAP12/TYROBP containing an immunoreceptor tyrosine-based activation motif (ITAM), thus, leading to microglial migration, phagocytosis and an oxidative burst. Loss-of-function mutations of the adaptor molecule DAP12/TYROBP are known to cause the human Nasu-Hakola disease, which is characterized by inflammatory neurodegeneration. Recently, variants of TREM2 were also causally-linked to Alzheimer’s disease and frontotemporal dementia. Those ITAM-signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif (ITIM)-signaling receptors such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs like Siglec-E of mouse microglia and Siglec-11 of human microglia recognize the sialic acid cap of healthy neurons leading to an ITIMsignaling in microglia that turns down the microglial proinflammatory responses, phagocytosis and the associated oxidative burst. Thus, immune function and radical production of microglia are fine tuned by this recognition system of paired ITAM- and ITIM-signaling receptors that sense the neuronal glycocalyx and modulate microglial neurotoxic function.
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