Characterisation and imaging of A-beta plaque formation and associated pathologies in transgenic mice
Final Report Abstract
Amyloid-β (Aβ) plaques and Lewy bodies mainly composed of α-synuclein (α-syn) are the major neuropathological hallmarks of Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. In 50% of AD patients these protein deposits frequently co-exist suggesting a direct interaction of Aβ and α-syn. However, the significance of this direct interaction for plaque formation remains elusive. We investigated the effect of α-syn on Aβ plaque formation by using intracerebral injections, grafting experiments and in vitro aggregation assays and identified a cross-inhibition of plaque formation by α-syn. Prevented Aβ deposition led to enhanced neurotoxic effects such as synapse loss at a very early stage of pathology most likely due to the accumulation of toxic Aβ species. The questions raised by this study show that the findings have implications for diseases with overlapping pathologies of Aβ and α-syn. Furthermore, we used in vivo two-photon microscopy to characterize in detail amyloid plaque development over time and to test the effect of prolonged treatment with a γ-secretase inhibitor on amyloid plaque pathology and plaque associated dendritic spine instability. This work extended in vivo studies of Aβ plaque formation providing a new, multiple fluorescent staining technique that allowed us to witness for the first time in vivo the phenomenon of plaque growth via the merger of plaque clusters. This plaque clustering theory of growth complements the uniform growth concept to culminate in a multi-dimensional model of plaque development.
Publications
- Monitoring protein aggregation and toxicity in Alzheimer’s disease mouse models using in vivo imaging. Methods 53 (3): 201-7. (2011)
Spires-Jones, T.L., de Calignon, A., Meyer-Luehmann, M., Bacskai, B.J. & Hyman, B.T.
- A peephole into the brain: neuropathological features of Alzheimer’s disease revealed by in vivo two-photon imaging. Frontiers in Psychiatry 2 (3): 26. (2012)
Liebscher, S. & Meyer-Luehmann, M.
- Clustering of plaques contributes to plaque growth in a mouse model of Alzheimer’s disease. Acta Neuropathologica 126 (2): 179-88. (2013)
McCarter, J.F., Liebscher, S., Bachhuber, T., Abou-Ajram, C., Hübener, M., Hyman, B.T., Haass, C. & Meyer-Luehmann, M.
(See online at https://doi.org/10.1007/s00401-013-1137-2) - Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nature Neuroscience 16 (5): 580-6. (2013)
Bardehle, S., Krüger, M., Buggenthin, F., Schwausch, J., Ninkovic, J., Clevers, H., Snippert, H.J., Theis, F.J., Meyer-Luehmann, M., Bechmann, I., Dimou, L., & Götz, M.
(See online at https://doi.org/10.1038/nn.3371) - Chronic γ-secretase inhibition reduces amyloid plaqueassociated instability of pre- and post-synaptic structures. Molecular Psychiatry 19 (8): 937-46. (2014)
Liebscher, S., Page, R.M., Käfer, K., Winkler, E., Quinn, K., Goldbach, E., Brigham, E.E., Quincy, D., Basi, G.S., Schenk, D.B., Steiner, H., Bonhoeffer, T., Haass, C., Meyer- Luehmann, M. & Hübener, M.
(See online at https://doi.org/10.1038/mp.2013.122) - Microglia as a critical player in both developmental and late-life CNS pathologies. Acta Neuropathologica 128 (3): 333-45. (2014)
Derecki, N.C., Katzmarski, N., Kipnis, J. & Meyer-Luehmann, M.
(See online at https://doi.org/10.1007/s00401-014-1321-z) - Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures. Scientific Reports 29 (5): 14624. (2015)
Hellwig, S., Masuch, A., Nestel, S., Katzmarski, N., Meyer-Luehmann, M. & Biber, K.
(See online at https://doi.org/10.1038/srep14624) - Inhibition of amyloid-β plaque formation by α-synuclein. Nature Medicine 21 (7): 802-7. (2015)
Bachhuber, T., Katzmarski, N., McCarter, J.F., Loreth, D., Tahirovic, S., Kamp, F., Abou- Ajram, C., Nuscher, B., Serrano-Pozo, A., Müller, A., Prinz, M., Steiner, H., Hyman, B.T., Haass, C. & Meyer-Luehmann, M.
(See online at https://doi.org/10.1038/nm.3885) - Label-free quantitative proteomics of mouse cerebrospinal fluid detects β-site APP cleaving enzyme (BACE1) protease substrates in vivo. Molecular and Cellular Proteomics 14 (10): 2550-63. (2015)
Dislich, B., Wohlrab, F., Bachhuber, T., Müller, S.A., Kuhn, P.H., Hogl, S., Meyer- Luehmann, M. & Lichtenthaler, S.F.
(See online at https://doi.org/10.1074/mcp.M114.041533) - Myeloid cells in Alzheimer’s disease: culprits, victims or innocent bystanders? Trends in Neuroscience 38 (10): 659-68. (2015)
Meyer-Luehmann, M. & Prinz, M.
(See online at https://doi.org/10.1016/j.tins.2015.08.011)
