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Active vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice

Molecular Psychiatry volume 18, pages 358–368 (2013)Cite this article

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Abstract

Serum antibodies against amyloid-β peptide (Aβ) in humans with or without diagnosis of Alzheimer's disease (AD) indicate the possibility of immune responses against brain antigens. In an unbiased screening for antibodies directed against brain proteins, we found in AD patients high serum levels of antibodies against the neuronal cytoskeletal protein ankyrin G (ankG); these correlated with slower rates of cognitive decline. Neuronal expression of ankG was higher in AD brains than in nondemented age-matched healthy control subjects. AnkG was present in exosomal vesicles, and it accumulated in β-amyloid plaques. Active immunization with ankG of arcAβ transgenic mice reduced brain β-amyloid pathology and increased brain levels of soluble Aβ42. AnkG immunization induced a reduction in β-amyloid pathology, also in Swedish transgenic mice. Anti-ankG monoclonal antibodies reduced Aβ-induced loss of dendritic spines in hippocampal ArcAβ organotypic cultures. Together, these data established a role for ankG in the human adaptive immune response against resident brain proteins, and they show that ankG immunization reduces brain β-amyloid and its related neuropathology.

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Acknowledgements

We thank Dr Annamaria Calella and Dr Sarah Hoey for helpful discussions (University of Zurich); Dr Burkhardt Seifert for help with statistical analysis; Dr Vann Bennett (Duke University Medical Center) for providing us with ankG and ankB recombinant proteins; Dr Uwe Konietzko (University of Zurich) for APP-citrine HEK293 cells; Dr Gang Yu (University of Texas) for HeLa cells expressing the Swedish mutation in APP; Esmeralda Gruber and Dr Anton Gielt for patient care and sampling (University of Zurich); Diana Bundschuh for human DNA genotypig and Sebastian Zurbriggen for help with cell culture (University of Zurich). Rebecca Derungs for help with himmunohistochemistry (University of Zurich). We thank Daniel Schuppli for animal care, Manuela Hitz and Bjorn Henz for technical help in behavioral experiments (University of Zurich). ACS was supported by the Novartis Foundation. AS was supported from the Swiss Commission for Research Partnerships with Developing Countries. LR acknowledges funding support from the Velux foundation, Bangerter Foundation and the Swiss National Science Foundation. MM and RMN were funded by the Swiss National Science Foundation SNSF 3200B0-112616/1, and the National Centre of Competence in Research NCCR ‘Neural Plasticity and Repair’. CH was supported by SNF 320030_125378 and SNF 33CM30_124111. CT was supported from DFG, Ta762/1-1. CB and MG were supported by DFG, (FOR885, GRK1459).

Author contributions

ACS, RMN and MM conceived the study. ACS, RMN, LR, MG, JG, and CH raised funds for the study. ACS, MM, AS, RMN, JB, LR, CT, CB, LK, MTF designed and performed the experiments. TW assisted with the experiments. ACS, RMN, MM, LR, CB, MG, ACS, RMN, MM, supervised the experiments and analyzed the data. ACS, MTF, MM, AS, RMN wrote the drafts of the manuscript. All authors edited the manuscript.

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Author notes

  1. M Merlini

    Present address: 4Current address: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.,

  2. A Shetty

    Present address: 5Current address: Department of Neurology, University of California, San Francisco, CA, USA.,

  3. J Grimm

    Present address: 6Current address: Neurimmune Therapeutics AG, Schlieren, Switzerland.,

  4. A C Santuccione, M Merlini and A Shetty: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Psychiatry Research, University of Zurich, Zurich, Switzerland

    A C Santuccione, M Merlini, A Shetty, C Tackenberg, M T Ferretti, J McAfoose, L Kulic, T Welt, J Grimm, C Hock & R M Nitsch

  2. Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, Zurich, Switzerland

    J Bali & L Rajendran

  3. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    C Bernreuther & M Glatzel

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  1. A C Santuccione
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Correspondence to A C Santuccione or R M Nitsch.

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A patent application that includes data from this manuscript was filed by the University of Zurich with ACS, MM, JG, CH and RMN listed as inventors.

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Santuccione, A., Merlini, M., Shetty, A. et al. Active vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice. Mol Psychiatry 18, 358–368 (2013). https://doi.org/10.1038/mp.2012.70

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