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Inhibition of amyloid-β plaque formation by α-synuclein

Abstract

Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB)1 and in more than 50% of AD cases2. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques2,3,4. Several studies report binding and coaggregation of Aβ and α-syn5,6,7, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn–containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695KM670/671NL and PSEN1L166P under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCAA30P (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.

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Figure 1: α-syn–containing preparations do not induce Aβ plaque formation in 6-week-old APPPS1 × Thy1-GFP transgenic mice.
Figure 2: Reduced hippocampal plaque load in APPPS1 × [A30P]aSYN transgenic mice.
Figure 3: Aβ seeding is decreased by α-syn.
Figure 4: Suppressed Aβ deposition and reduced Aβ-42 fibril formation in the presence of α-syn.

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Acknowledgements

We thank A. Wenninger-Weinzierl, S. Diederich, S. Waldkirch and R. Ziegler for technical assistance. This work was supported by the Emmy Noether Program of the Deutsche Forschungsgemeinschaft (M.M.-L.), the European Research Council (ERC) under the EU′s Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. 321366-Amyloid (advanced grant to C.H.), the Kompetenznetz Degenerative Demenzen of the German Federal Ministry of Education and Research (C.H. and H.S.), the Hans and Ilse Breuer Foundation (M.M.-L.), the Graduate School of Systemic Neurosciences (J.F.M.) and the International Max Planck Research School (J.F.M.). We also would like to thank T. Iwatsubo (University of Tokyo) for the phospho-Ser129 antibody, E. Kremmer (Ludwig-Maximilians University, Munich) for the 3552 and 15G7 antibodies, N. Exner (Ludwig-Maximilians University, Munich) for the α-synuclein cDNA constructs and M. Jucker (University of Tübingen) for generously providing the APPPS1 transgenic mice.

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T.B., C.H. and M.M.-L. conceived the experiments. T.B., N.K., J.F.M., D.L., S.T., C.A.-A., B.N., F.K. and A.S.-P. performed experiments. B.T.H. provided human brain samples. A.M., D.L. and M.P. performed electron microscopy. H.S., S.T., F.K. and A.S.-P. provided important experimental guidance. T.B., J.F.M., H.S., B.T.H., C.H. and M.M.-L. discussed the results. T.B., J.F.M. and M.M.-L. wrote the manuscript. M.M.-L. supervised the project and coordinated the study. All authors edited the paper.

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Correspondence to Melanie Meyer-Luehmann.

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Bachhuber, T., Katzmarski, N., McCarter, J. et al. Inhibition of amyloid-β plaque formation by α-synuclein. Nat Med 21, 802–807 (2015). https://doi.org/10.1038/nm.3885

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