The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand is open to change in order to store information, but at the same time is vulnerable to damage from injury, pathogen invasion or neurodegenerative diseases (NDs). Microglia representing the brain's innate immune system, execute a number of physiological functions important for the maintenace of tissue homeostasis, synapse remodelling and neurotrophic factor secretion. In NDs and more particular upon chronic exposure to aberrant proteins or RNA, microglia mount a persistent sterile and proinflammatory immune response and neglect their physiological and beneficial functions. This chronic innate immune activation contributes to disease development and progression. The central aim of the present proposal is to study this innate immune activation by combining a system biological approach and functional and functional analysis of the three most frequent NDs: Alheimer's disease (AD), Parkinson's disease (PD) and Fronto-Temporal-Dementia (FTD), which all have been described to harbour an inflammatory disease component.
Microglial and neuronal gene network hubs, modules and checkpoints will be first analyzed on a cellular level using disease relevant immunostimulants. Next, these findings will be replicated using state-of -the-art animal models of AD, PD and FTD. Our goal is to identify shared and overlapping networks and compare those to changes of functional readouts. Importantly, we will valorize our findings by analysing human microglial cells and brain tissue derived from AD/PD/FTD patients. Furthermore we will assess whether identified network changes correlate to disease phenotypes and progression using CSF samples from AD,PD and FTD patients. The unique strength of our research-consortium is that it combines different expertise from the field of neurology, experimental neuroscience, neuropathology and systems biology. It is essential to reveal these common network hubs and checkpoints to identify new diagnostic biomarkers but also to gain insights into prevention and early treatment of these NDs.
The internal workspace for consortium members can be found here.
TU Braunschweig and
Helmholtz Center for Infection Research (HZI)
VU Univerity medical center
Depts. of Clinical Chemistry and Psychiatry
Amsterdam, The Netherlands
Dept. of Medicine
Karolinska Institutet & Karolinska University Hospital
Center for Molecular Medicine
Michael T. Heneka
German Center for Neurodegenerative Diseases and
University of Bonn
Dept. of Neurology
This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND: France, Agence National de la Recherche; Germany, Federal Ministry of Education and Research (BMBF; funding code 01ED1505A); Italy, Ministry of Education, Universities and Research; Netherlands, The Netherlands Organisation for Health Research and Development; Sweden, Swedish Research Council (VR).
The EU Joint Programme – Neurodegenerative Disease Research (JPND) is the largest global research initiative aimed at tackling the challenge of neurodegenerative diseases. JPND aims to increase coordinated investment between participating countries in research aimed at finding causes, eveloping cures, and identifying appropriate ways to care for those with neurodegenerative diseases - www.jpnd.eu