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β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease

Nature Medicine volume 19, pages 43–49 (2013)Cite this article

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Abstract

β-arrestins are associated with numerous aspects of G protein–coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2−/− mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ40 and Aβ42. Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β2-adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.

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Figure 1: Expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, and overexpression and silencing of β-arrestin 2 differentially regulate Aβ accumulation.
Figure 2: Endogenous Aβ generation is reduced in β-arrestin 2–deficient mice.
Figure 3: The C-terminal domain of GPR3 modulates the interaction with β-arrestin 2 and Aβ generation.
Figure 4: β-arrestin 2 and the active γ-secretase complex are enriched in DRMs.
Figure 5: β-arrestin 2 interacts with the Aph-1a subunit of the γ-secretase complex.
Figure 6: β-arrestin 2 contributes to Aβ generation in an Alzheimer's disease transgenic mouse model.

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Acknowledgements

We are grateful to R.J. Lefkowitz and S. Ahn (Duke University Medical Center, Durham, North Carolina, USA) for the generous gift of the β-arrestin 2 wild-type and knockout mouse embryonic fibroblasts, the Arrb1−/− and Arrb2−/− mice, the β-arrestin 2–GFP-Flag cDNA and helpful discussion. We thank M. Jucker (University of Tübingen, Germany) for the gift of APP/PS1 transgenic mice. We greatly appreciate the kind gift of human control and Alzheimer's disease brain samples from K. Bossers and D.F. Swaab (Netherlands Institute for Neuroscience, Amsterdam, The Netherlands) and C. Troakes (the London Neurodegenerative Diseases Brain Bank, London, UK). We thank M. Mercken (Johnson & Johnson Pharmaceuticals Research and Development, Beerse, Belgium) for the antibodies to Aβ. We are grateful to Y. Li (Memorial Sloan Kettering Cancer Center, New York, USA) for the kind initial gift of JC-8. This work was supported by a Mentored New Investigator Research grant from the Alzheimer's Association to A.T., the Fund for Scientific Research Flanders, KU Leuven, a Methusalem grant from the KU Leuven and the Flemish government, and the Foundation for Alzheimer Research (SAO/FRMA) to B.D.S. B.D.S. is the Arthur Bax and Anna Vanluffelen chair for Alzheimer's disease.

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Authors and Affiliations

  1. Vlaams Instituut voor Biotechnologie (VIB) Center for the Biology of Disease, Leuven, Belgium

    Amantha Thathiah, Katrien Horré, An Snellinx, Elke Vandewyer, Yunhong Huang, Marta Ciesielska, Gerdien De Kloe, Sebastian Munck & Bart De Strooper

  2. Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, Belgium

    Amantha Thathiah, Katrien Horré, An Snellinx, Elke Vandewyer, Yunhong Huang, Marta Ciesielska, Sebastian Munck & Bart De Strooper

  3. Neuroscience Department, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, Beerse, Belgium

    Gerdien De Kloe

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Contributions

A.T. and B.D.S. designed the experiments and wrote the manuscript. A.T., K.H., A.S., E.V. and Y.H. conducted the experiments. M.C. conducted the qPCR experiments. G.D.K. synthesized JC-8. S.M. conducted the immunofluorescence image analysis.

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Correspondence to Amantha Thathiah or Bart De Strooper.

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Competing interests

B.D.S. receives research funding from and is a consultant for Janssen Pharmaceutica, Beerse, Belgium, Envivo, and Remynd, Leuven, Belgium. A.T. and B.D.S. are inventors on a patent that links β-arrestin to GPR3 and the γ-secretase complex, which is owned by VIB.

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Thathiah, A., Horré, K., Snellinx, A. et al. β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med 19, 43–49 (2013). https://doi.org/10.1038/nm.3023

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