|Name||Dr. Melanie Meyer-Lühmann|
|Date of Birth||31.03.2007|
|since 2008||Independent group leader at the Adolf-Butenandt-Institut, Ludwig-Maximilians-University Munich, Germany|
|2005-2008||Postdoctoral fellow at the Massachusetts General Institute for Neurodegenerative Disease (MIND), Harvard Medical School, Boston, USA, with Prof. Bradley T. Hyman|
|2004||Postdoctoral fellow at the Hertie Institute of Clinical Brain Research, Tuebingen, Germany, with Prof. Mathias Jucker|
|2004||PhD in Neurobiology, grade: summa cum laude, University of Basel, Switzerland|
|2000-2004||PhD Thesis at the University of Basel, Switzerland with Prof. Mathias Jucker. Title: Experimental approaches to study cerebral amyloidosis in a transgenic mouse model of Alzheimer`s disease.|
|2000||M.S. (Diplom) in Biology, grade: very good, University of Freiburg, Germany|
|1999-2000||M.S. (Diplom) Thesis at the University of Michigan, Ann Arbor, USA with Prof. John Wayne Aldridge. Title: Extracellular recordings in the substantia nigra pars reticulate during normal grooming behavior in rats.|
|1993-1999||Undergraduate and graduate studies of Biology at the University of Freiburg, Germany|
A number of degenerative neurological and systemic diseases are characterized by the accumulation of specific proteins in tissues. In the nervous system, these proteopathies include Alzheimer's disease (AD) and Parkinson's disease (PD) among others. In order to provide a meaningful therapy, it is essential to understand the pathogenesis of these diseases, particularly in their early stages. Since some patients show clinical and pathological features of AD and PD, it has been speculated that both diseases share overlapping pathogenic pathways and might even influence each other. During the course of AD, neurons lose synapses and specifically dendritic spines. They also suffer from changes in neurite architecture such as curvature caused by senile plaques. Since synapses and neurites are very plastic structures, they have the potential to recover after treatments, giving hope for some functional recovery.
I have previously shown that intracerebral injection of A-beta-containing human or transgenic mouse brain extracts can induce cerebral A-beta-amyloidosis and associated pathology in young pre-depositing APP transgenic mice and that this amyloid induction is time and concentration dependent (Meyer-Luehmann et al., 2006). This induced amyloidosis can effectively be blocked when brain extracts are mixed with anti-A-beta antibodies or by A-beta-immunization of the host. Although standard immunohistological approaches are powerful, they only reveal a snapshot of information. Taking advantage of multiphoton imaging where neuronal processes, amyloid plaques and blood vessels can be observed simultaneously in the living mouse in real time, I was able to study the temporal relationship between plaque formation and the changes in local neuritic architecture. Imaging on a daily basis uncovered that plaques appear relatively suddenly, between one imaging session and the next, 24 hours later. After a plaque appears, progressive neuritic changes lead to increasingly curved, dysmorphic neurites over the next few days to weeks within the immediate vicinity of plaques (Meyer-Luehmann et al., 2008). These results suggest that plaque-related neuritic changes are a direct consequence of dense-cored plaque formation and therefore a later event in AD pathogenesis. Imaging techniques such as 2-Photon microscopy allow visualization and characterization of A-beta plaques and neuritic changes as well as paradigms for preventing or reversing the deposits and associated pathologies. An effective analysis of amyloid-beta clearance is therefore possible in the living mouse, where plaques can be observed before, during and after treatment. I have helped to develop imaging approaches that allow the observation of amyloid-beta deposits chronically in the brains of living, APP transgenic mice using multiphoton microscopy.
The objective of future studies is to promote the understanding of the kinetics of plaque formation and associated neuritic abnormalities as well as the mechanism involved in the induction of A-beta aggregation and propagation in vivo and to suggest treatments that will restore neuritic morphology. Specifically I suggest to characterize early stages of A-beta plaque formation and to visualize associated neuronal dysfunction. Furthermore I would like to test the hypothesis that beta-synuclein would interact with A-beta and that A-beta protein aggregation and deposition can be induced by beta-synuclein. Another project will test the idea that blocking A-beta synthesis will lead to a structural recovery of neurites.
The proposed studies will unequivocally give new insights not only into the kinetics of amyloid plaque formation but also into the associated neuronal dysfunction and therefore provide valuable information for therapeutic intervention.
1. Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781-4 (2006).
2. Meyer-Luehmann, M. et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451, 720-4 (2008).
1. Koffee, R.M., Meyer-Luehmann, M., Hashimoto, T., Adams, K.W., Mielke, M.L., Garcia-Alloza, M., Micheva, K.D., Smith, S.J., Kim, M.L., Lee, V.M., Hyman, B.T., Spires-Jones, T.L. (2009). Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. ProcNatlAcadSci 106 (10): 4012-7.
2. Koenigsknecht-Talboo, J., Meyer-Luehmann, M., Parsadanian, M., Garcia-Alloza, M., Finn, M.B., Hyman, B.T., Bacskai, B.J. and Holtzman, D.M. (2008). Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J Neurosci. 28(52):14156-64.
3. Spires-Jones, T.L., Mielke, M.L., Rozkalne, A., Meyer-Luehmann, M., de Calignon, A., Bacskai, B.J., Schenk, D. and Hyman, B.T. (2008). Passive immunotherapy increases structural plasticity in a mouse model of Alzheimer disease. Neurobiol Dis. 2009 Feb;33(2):213-20. Epub 2008 Nov 6.
4. Jones, P.B., Rozkalne, A., Meyer-Luehmann, M., Spires-Jones, T.L., Makarova, A., Kumar, A.T., Berezovska, O., Bacskai, B.J. and Hyman, B.T. (2008). Two postprocessing techniques for the elimination of background autofluorescence for fluorescence lifetime imaging microscopy. J Biomed Opt 13 (1): 014008.
5. Meyer-Luehmann, M., Spires-Jones, T.L., Prada, C., De Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D.M., Bacskai, B.J. and Hyman, B.T. (2008). Rapid appearance and local toxicity of amyloid plaques in a mouse model of Alzheimer’s disease. Nature 451, 720-4.
6. Bolmont, T., Clavaguera, F., Meyer-Luehmann, M., Herzig, M.C., Radde, R., Staufenbiel, M., Lewis, J., Hutton, M., Tolnay, M. and Jucker, M. (2007). Induction of tau pathology by intracerebral infusion of amyloid--containing brain extract and by amyloid in APP X tau transgenic mice. Am J Pathol 171, 2012-20.
7. Spires-Jones, T.L., Meyer-Luehmann, M., Osetek, J.D., Jones, P.B., Stern, E.D., Bacskai, B.J. and Hyman, B.T. (2007). Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model. Am J Pathol 171, 1304-11.
8. Garcia-Alloza, M., Dodwell, S.A., Meyer-Luehmann, M., Hyman, B.T. and Bacskai, B.J. (2006). Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J Neuropathol Exp Neurol 65, 1082-9.
9. Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A.L., Vigouret, J.M., Paganetti, P., Walsh, D.M., Mathews, P.M., Ghiso, J., Staufenbiel, M., Walker, L.C. and Jucker, M. (2006). Induction of cerebral -amyloidogenesis is governed by agent and host. Science 313, 1781-4.
10. Spires, T.L., Meyer-Luehmann, M., Stern, E.D., McLean, P.J., Skoch, J., Nguyen, P.T., Bacskai, B.J. and Hyman, B.T. (2005). Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy.
J Neurosci 25, 7278-87.
11. Sykova, E., Vorisek, I., Antonova, T., Mazel, T., Meyer-Luehmann, M., Jucker, M., Hajek, M., Or, M. and Bures, J. (2005). Changes in extracellular space size and geometry in APP23 transgenic mice: A model of Alzheimer’s disease. Proc Natl Acad Sci USA 102, 479-84.
12. Mueggler, T., Meyer-Luehmann, M., Rausch, M., Staufenbiel, M., Jucker, M., and Rudin, M. (2004). Restricted diffusion in the brain of transgenic mice with cerebral amyloidosis. Eur J Neurosci 20, 811-7.
13. Meyer-Luehmann, M., Stalder, M., Herzig, M. C., Kaeser, S. A., Kohler, E., Pfeifer, M., Boncristiano, S., Mathews, P. M., Mercken, M., Abramowski, D., Staufenbiel, M. and Jucker, M. (2003). Extracellular amyloid formation and associated pathology in neural grafts. Nat Neurosci 6, 370-377.
14. Meyer-Luehmann, M., Thompson, J. F., Berridge, K. C., and Aldridge, J. W. (2002). Substantia nigra pars reticulata neurons code initiation of a serial pattern: implications for natural action sequences and sequential disorders.
Eur J Neurosci 16, 1599-1608.