|Name||Dr. Andre Fischer|
|Place of Birth||Flensburg|
|Date of Birth||12.06.1974|
|since 2007||Independent Group leader at the European Neuroscience Institute Göttingen, Head of the Laboratory for Aging and Cognitive Diseases|
|since 2006||Elected Member of the ENI-Network of European Young Investigators|
|since 2006||Affiliate at Massachusetts Institute of Technology, Picower Center for Learning and Memory, Cambridge, Massachusetts, U.S.A.|
|2005-2006||Postdoctoral Research Fellow at Massachusetts Institute of Technology, Picower Center for Learning and Memory, Cambridge, Massachusetts, U.S.A. Prof. Li-Huei Tsai|
|2003-2006||Postdoctoral Research Fellow at Harvard Medical School, Department of Pathology, Boston, Massachusetts, U.S.A. Prof. Li-Huei Tsai|
|2002-2003||Postdoctoral Research fellow, Max Planck Institute for Experimental Medicine, Göttingen, Germany, Prof. Jelena Radulovic|
|2002||PhD, summa cum laude, Georg-August University Göttingen|
|1999-2000||Diploma Degree, Max Planck Institute for Experimental Medicine, University Göttingen|
Targeting epigenetic gene-expression as a therapeutic strategy to treat age-associated memory impairment and Alzheimer’s disease
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although the etiology of sporadic AD is not well understood, age is the single most risk factor. Therefore, as life expectancies continue to rise, AD is becoming tragically common. Despite intensive studies no cure is yet available.
I hypothesize that a better understanding of age-associated memory impairment (AAMI) will help to elucidate the pathogenesis of AD and vice versa. Interestingly, several lines of evidence indicate that AAMI and AD are accompanied by the selective down-regulation of genes involved with synaptic function. The reason for this down-regulation is not well understood but our preliminary data point to the possibility that deregulation of epigenetic mechanisms could be a common feature in neurodegenerative diseases and may provide very suitable therapeutic target.
The two most studied epigenetic phenomena are DNA-methylation and Histone-tail modifications, which build up discrete patterns of chemical marks recognized and bound by other proteins. The acetylation of histones is regulated by histone-acetyl transferases (HAT) and histone-deacetylases (HDAC), that transfer or remove acetyl-groups on specific lysine residues on histone-tails, respectively.
Recent reports, including our data, have shown that inhibition of HDAC activity can attenuate neuronal cell death and improve memory function. To what extend deregulation of epigenetic processes is involved in the pathogenesis of AD is however not understood.
In this project I suggest to employ biochemical, epigenetic, pharmacological and behavioral experiments to investigate how changes in chromatin structure and epigenetic gene-expression contribute to the pathogenesis of AAMI and AD. The therapeutic potential of targeting chromatin-modifying enzymes directly will be analyzed by a combination of pharmacological and genetic approaches.
Fischer , A. Epigenetics: Bottleneck of neurodegenerative diseases? Neuroforum, 2009, in press
Schrick, C, Fischer, A., Srivastava, DP, Tronson, NC., Penzes, P., Radulovic, J. (2007) N-Cadherin regulates cytoskeletally-associated IQGAP/ERK signaling and memory formation. Neuron, 55(5):786-798.
Tronson NC, Schrick C, Fischer A., Sananbenesi F, Pages G, Pouyssegur J, Radulovic J. Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior. Neuropsychopharmacology. (2007) Aug 22; Epub ahead of print
Sananbenesi, F. Fischer, A., Wang, X., Schrick, C. Neve, R. Radulovic, J. Tsai, L.H. (2007) A hippocampal Cdk5 pathway regulates the extinction of contextual fear. Nature Neuroscience, 15th July, Epub ahead of print
Kim D., Nguyen M.D., Dobbin M.M., Fischer A., Sananbenesi F. , Rodgers J.T., Delalle I., Baur J.A., Sui G., Armour S., Puigserver P., Sinclair D.A., Tsai L.H. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J, June 27, Epub ahead of print
Fischer A., Sananbenesi F., Wang X., Dobbin M., Tsai L.H. (2007) Recovery of learning and memory is associated with chromatin remodelling. Nature 447:178-82. Epub 2007 Apr 29.
Fischer A., Radulovic M, Schrick C, Sananbenesi F, Godovac-Zimmermann J, Radulovic J (2006) Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior. Neurobiology of Learning and Memory 87:149-5
Shu T., Tseng H.C., Zhou Y., Fischer A., Stern P., Coquelle F., Reiner O., Tsai L.H. (2006). Doublecortin-like Kinase Controls Neurogenesis by Regulating the Mitotic Spindle. Neuron, 49:25-39
Fischer A., Sananbenesi F., Pang P.T., Lu B., Tsai L.H. (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus dependent memory. Neuron, 48: 825-838.
Park S.K., Nguyen M.D., Fischer A.[shared co-authorship], Affar E.B, Luke, M., Dieffenbach B., Shi, Y, Tsai L.H. (2005). Modulation of Dopamine Signaling by Prostate Apoptosis Response 4 via Direct Interaction with Dopamine D2 Receptor. Cell, 122:275-287
Fischer A., Sananbenesi F., Schrick C., Spiess J., Radulovic J. (2004) Distinct roles of hippocampal protein synthesis and actin rearragnement in extinction of conditioned fear. J.Neurosci., 24:1962–1966
Sananbenesi F., Fischer A., Schrick C., Spiess J., Radulovic J. (2003) Corticotropin-releasing factor receptor 2 induces mitogen-activated protein kinase signaling in the hippocampus: A possible link between stress and fear memory. J.Neurosci., 36:11436 –11443
Fischer A., Sananbenesi F., Spiess J., Radulovic J. (2003) Cdk5 in the adult non-demented brain. Current drug targets CNS, 2, 61-72
Fischer A., Sananbenesi F., Spiess J., Radulovic J. (2003) Cdk5: a novel role in learning and memory. NeuroSignals, 12, 200-208.
Fischer A., Sananbenesi F., Schrick C., Spiess J., Radulovic J. (2003) Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5. Neuropharmacology, 44, 1089-1099
Sananbenesi F., Fischer A. [shared first-authorship], Schrick C., Spiess J., Radulovic J. (2002) Phosphorylation of hippocampal Erk-1/2, Elk-1, and p90-Rsk-1 during contextual fear conditioning: interactions between Erk-1/2 and Elk-1. Mol. Cell. Neurosci., 3, 463-476
Fischer A., Sananbenesi F., Schrick C., Spiess J., Radulovic J. (2002) Cyclin-dependent kinase 5 is required for associative learning. J. Neurosci., 9, 3700-3007
Radulovic J., Fischer A., Katerkamp U., Spiess J. (2000) Role of regional neurotransmitter receptors in corticotropin-releasing factor (CRF)-mediated modulation of fear conditioning. Neuropharmacology, 39, 707-710
Sydow S., Flaccus A., Fischer A., Spiess J. (1999) The role of the fourth extracellular domain of the rat corticotropin-releasing factor receptor type 1 in ligand binding. Eur. J. Biochem., 259, 55-62
Fischer A. & Tsai L.H. (2008) Counteracting molecular pathways regulate the reduction of fear: Implications for the treatment of anxiety diseases. In: Neurobiology of Post-Traumatic stress disorders, Ed. Peter Shiromani, Terrence Keane, Josef LeDoux, Human Press, in press
Fischer A. & Tsai L.H. (2008) Cycline dependent kinase 5 (Cdk5): linking synaptic plasticity and neurodegeneration. In: Cycline dependent kinase 5 (Cdk5), Ed. Nancy Ip, Spinger Science and Buisness Media LLC, in press
Radulovic J., Kammermeier, J., Fischer A., Spiess J. (1999) Lernen, Angst und Streß: Molekulare Verknüpfungen. In Körper, Seele, Trauma. Biologie, Klinik und Praxis. Ed. Streeck-Fischer A., Sachsse U., Özkan L. Vanderhoeck & Ruprecht, Göttingen, S.132-142
Articles discussing the work of the group:
Sweatt J.D. (2007) Behavioral Neuroscience: Down memory lane, Nature, 447: 151-152
Mangan K.P., Levenson J.M (2007) Turning back the clock on neurodegeneration. Cell, 129, 851-853
Pizzorusso T et al, (2007) A richness that cures. Neuron 54(4):508-10.
LaFerla FM, Kitazawa M. (2005) Antipodal effects of p25 on synaptic plasticity, learning, and memory--too much of a good thing is bad. Neuron. 48:711-712.
Guo Q. (2006) When good Cdk5 turns bad. Sci Aging Knowledge Environ. ;2006(5):pe5.
Bibb JA. (2005) Decoding dopamine signaling. Cell. 122:153-155.