Michael T. Heneka, PhD, MD
Prof. of Clinical Neuroscience
Dept. of Neurodegenerative Disease and Gerontopsychiatry / Neurology; German Center for Neurodegenerative Disease (DZNE), University of Bonn Medical Center, Germany
I. The research group
Our research group is focused on preclinical and clinical studies of neurodegenerative diseases. The main interest is the understanding of molecular and physiological mechanisms underlying inflammatory processes occurring during variety of neurodegenerative diseases, with a major focus on Alzheimer’s disease, septic encephalopathy, multiple sclerosis... The research investigations on the pathophysiology of neurodegenerative diseases include: study of the brain and peripheral innate and adaptive immune activation and responses, understanding of the mechanisms underlying the transition from chronic to acute neuroinflammation, deciphering interactions of acquired risk factors and the involved in ApoE mediated pathways in Alzheimer's Disease etc. Current clinical research is focused on various aspects of neuroinflammation involved in neurodegenerative and cerebrovascular diseases with the goal of developing new medical intervention programs.
Funding ongoing projects include:
- InMind-Imaging of Neuroinflammation in Neurodegenerative Diseases
- TracInflam - Transition from acute to chronic neuroinflammation
- InCure - Innate Immune Activation in Neurodegenerative Diseases
- DACAPO-AD Deciphering Interactions of Acquired Risk Factors and ApoE mediated Pathways in Alzheimer's Disease
- MADGIC- Generation of Improved Cellular and Animal Models for Identification of Disease Phenotype and New Therapeutic Targets of Alzheimer’s disease
Several animal models are routinely used in our laboratory to answer specific research questions: APP/PS1 (AD), NALP3-/- and APPPS1xNALP3-/-, CX3CR1-GFP, NOS2-/-, TLRs -/-, Apoe -/-, CX3CR1-GFP-Cre-GFP and CX3CR1-yfp-cRE-yfp (optogenetic animals)… Primary microglia, astrocytes and neurons are routinely generated from these different models to perform several in vitro stimulation assays, perform screening of large panel of molecules... In addition to these animal models, a broad variety of techniques are available in the laboratory. This includes the basic infrastructures as Tecan plate reader, fluorescence microscope, flow Cytometer (BD FACS ScantoII), LI-COR fluorescent membrane imaging but also the live microscope, 2-photons microscope, HPLC instrument, Biorad spot picker, Typhon phosphorimager/ scanner etc. We have also the opportunity to use other technologies available in the core facility of the Research center (German Center for Neurodegenerative Disease (DZNE)) and the hospital (University of Bonn Medical Center).
II. Participation in the MADGIC project
Our overall task in the JPND MADGIC is to characterize microglia, microglia-like cells and microphages in terms of phenotypes, functions and their contribution to AD related phenotypes, both in-vitro and in-vivo conditions.
The first part of the work consists of the generation of microglia/macrophage-like cells from AD monocytes (sAD and FAD). This will enable us to perform comparative studies between the cell types generated (from iPSCs vs monocytes) and will also be a useful tool in solving unknown dynamic aspects of the human disease.
Protocols to generate macrophages from monocytes and to test their functional activity are already available in our lab. We attempt to generate microglia-like cells from the monocytes, reaching thereby a further differentiation “stage” of monocytes. The generation of these induced microglia-like cells was achieved in the presence of several growth factors (IL34, GM-CSF, MCSF, MCP1, NGF-β) and medium supplement (astrocytes conditioned medium) during 14 days. The cells were monitored and analyzed for their morphology (microscopy) and surface molecule expression (flow cytometry) and compared to macrophages during the differentiation process.
Despite the use of different combination of growth factors, media and culture conditions, we have not been able to generate microglia-like cells from monocytes. The cells show macrophages phenotypes characteristics (shape and cell surface markers expression)
The next step of this task is to start the inclusion of patients, generate macrophage derived blood monocytes and perform their phenotypic and functional characterization.
A second part of the work consists of the characterization of the phenotypes and functions of the iPSCs derived microglia-like cells. Our laboratory does not have the expertise on iPSCs handling. Thus, an exchange with the laboratory of Dr. Tarja Malm is planned from March-April 2017 for 30 to 45 days. The aim of this visit, for the post-doctoral fellow, is to have an excellent training on microglia-like cell generation. This visit will also allow a transfer of technology and knowledge between different labs of the consortium, one of the major objectives of this JPND MADGIC project.
III. Key publications relevant for the project
1. Heneka MT, Fink A, Doblhammer-Reiter G. Effect of pioglitazone medication on the incidence of dementia. (2015). Ann. Neurol. 78: 284-94.
2. Heneka MT, Golenbock D, Latz E Neuroinflammation in Alzheimer’s disease. (2015). Nat. Immunol. 16:229-236.
3. Kummer MP, Schwarzenberger R, Sayah-Jeanne S, Dubernet M, Walczak R, Hum DW, Schwartz S, Axt D, Heneka MT. Pan-PPAR modulation effectively protects APP/PS1 mice from amyloid deposition and cognitive deficits. Mol Neurobiol. 2015 Apr;51(2):661-71
4. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira- Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. (2013). Nature. 493: 674- 678.