Regulation of microglia-mediated neuroinflammation by microneurotrophins

• Applicant: Privatdozentin Dr. Vasileia Ismini Alexaki
• Subject Area: Endocrinology, Diabetology, Metabolism ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264619211

Inflammation is a major component of neurodegenerative diseases. A critical regulator of neuroinflammation is the balance between M1 polarized microglial cells, which induce pro-inflammatory responses, and the anti-inflammatory resting M2 subtype. The balance between M1 and M2 microglial cells is regulated by the microenvironment of the central nervous system (CNS). This microenvironment includes neurotrophins, such as the Nerve Growth Factor (NGF) and neurosteroids, such as dehydroepiandrosterone (DHEA). We have recently shown, that DHEA and its analogue, BNN27 that cannot be metabolized to androgen or estrogen, exert potent neuroprotective effects through activation of the NGF receptors TrkA and p75NTR, thus acting as microneurotrophins. In the present study we will investigate the effects of the (micro)neurotrophins NGF, DHEA and BNN27 on microglia-mediated neuroinflammation and microglial cell polarization, as well as the underlying cellular mechanisms. Furthermore we will focus on the role of the NGF receptors, TrkA and p75NTR, in microglia-driven inflammation by engaging genetically modified mice allowing conditional deletion of these receptors in different models of neuroinflammation: an Alzheimers disease, a Parkinsons disease and a multiple sclerosis model. We expect that these findings will significantly improve our understanding of the link between neuroinflammation and neurodegeneration and will provide novel important therapeutic insights.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Triantafyllos Chavakis; Christine Mund