BBB seminar: Greg Lemke
TAM receptors in the brain
Tuesday, May 15, 14.30 - NB! Day, Auditorium 2
BBB seminar and Biokjemisk Kollokvium (NBS, Bergen Division)
Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
Unrestrained inflammation of the central nervous system (CNS) underlies many neurodegenerative diseases, including Alzheimer’s Disease (AD), Multiple Sclerosis (MS), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Key cells for the production of, and response to neuroinflammation are microglia, the distinctive tissue macrophages of the CNS. These immune sentinels subserve multiple functions, but are best known for the roles they play in immune surveillance and the phagocytic removal of apoptotic cells (ACs) and microbes. We have recently shown that microglia express two members of the TAM family of receptor tyrosine kinases (RTKs) – high levels of Mer and low levels of Axl – under homeostatic conditions, and that these receptors play key roles in the phagocytosis of the ACs that are generated during adult neurogenesis and in response to viral infection. We have also shown that microglial Axl is strongly up-regulated both in response to neuroinflammatory stimuli and in a transgenic mouse model of PD. Now, microglial Axl mRNA has been found to be dramatically up-regulated in both AD and its mouse models, and an elevated level of the soluble Axl ectodomain in cerebrospinal fluid (CSF) and blood has been found to be among the most reliable biomarkers of human AD progression. A recent report classifies Axl as an ‘AD-associated gene’. We have therefore examined regulation of components of the TAM system in mouse models of both AD and ALS, and are currently performing both genetic and pharmacological perturbations of TAM signaling in these models. Our initial results suggest that the TAMs play critical roles in both the inhibition of AD-triggered neuroinflammation and in the phagocytosis of amyloid b-associated cells and membranes.
Chairperson: James B. Lorens, Department of Biomedicine