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Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation

Nature Medicine volume 12, pages 1390–1396 (2006)Cite this article

Abstract

Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the γ-secretase catalytic subunit, can affect amyloid-β (Aβ) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how γ-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including β2-adrenergic receptor (β2-AR). Here we report that activation of β2-AR enhanced γ-secretase activity and thus Aβ production. This enhancement involved the association of β2-AR with presenilin-1 and required agonist-induced endocytosis of β2-AR and subsequent trafficking of γ-secretase to late endosomes and lysosomes, where Aβ production was elevated. Similar effects were observed after activation of δ-opioid receptor. Furthermore, chronic treatment with β2-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, β2-AR activation can stimulate γ-secretase activity and amyloid plaque formation, which suggests that abnormal activation of β2-AR might contribute to Aβ accumulation in Alzheimer disease pathogenesis.

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Figure 1: GPCR stimulation increases Aβ production in cell lines and primary hippocampal cultures.
Figure 2: β2–AR stimulation enhances γ-secretase activity.
Figure 3: Receptor endocytosis is associated with enhanced γ-secretase activity.
Figure 4: Increased γ-secretase and Aβ in endocytic compartments.
Figure 5: Enrichment of γ-secretase requires endocytic transport.
Figure 6: Enhanced γ-secretase activity and Aβ production, and accelerated amyloid plaque formation in vivo.

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Acknowledgements

We thank M.M. Poo, D.S. Li, H. Zheng, Z. Zhang and L. Pu for comments on the manuscript; Y.X. Zeng, G. Niu, P. Xia, Y.Y. Wang, W.B. Zhang and Y. Sun for technical support; R.J. Lefkowitz (Duke University Medical Center) for β2-AR TYY plasmid; S.L. Schmid (The Scripps Research Institute) for Dyn K44A plasmid; S. Marullo (The Cochin Institute) for β3-AR plasmid; P. Wang (University of Minnesota School of Medicine) for various Rab5 and Rab7 plasmids; and B. De Strooper (Katholieke Universiteit Leuven) and H.X. Xu (Burnham Institute for Medical Research) for wild-type and Psen1−/−Psen2−/− mouse embryonic fibroblasts. This research was supported by grants from the Ministry of Science and Technology (2003CB515405 and 2005CB522406) and the National Natural Science Foundation of China (30021003 and 30228018).

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  1. Yanxiang Ni and Xiaohui Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,

    Yanxiang Ni, Xiaohui Zhao, Guobin Bao, Lin Zou, Lin Teng, Zhu Wang & Gang Pei

  2. Graduate School of the Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China

    Yanxiang Ni, Xiaohui Zhao, Guobin Bao, Lin Zou, Lin Teng, Zhu Wang & Gang Pei

  3. Department of Medical Genetics, Third Military Medical University, 30 Gao Tan Yan, Chongqing, 400038, China

    Min Song, Jiaxiang Xiong & Yun Bai

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Contributions

This study was designed by Y.N., X.Z. and G.P. The experiments were performed by Y.N. and X.Z. G.B. and L.T. contributed to the in vivo experiments. L.Z. and Z.W. contributed to the in vitro experiments. M.S., J.X. and Y.B. provided the APPswe/PS1ΔE9 mice. G.P. supervised the project. Y.N., X.Z. and G.P. contributed to the writing of the paper.

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Correspondence to Gang Pei.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Stimulation of endogenous DOR enhances γ-secretase activity. (PDF 138 kb)

Supplementary Fig. 2

Time course of γ-secretase activity after stimulation of β2AR. (PDF 260 kb)

Supplementary Fig. 3

Pertussis toxin does not affect DOR-induced enhancement of γ-secretase activity. (PDF 221 kb)

Supplementary Fig. 4

Transferrin can not induce γ-secretase activity enhancement. (PDF 230 kb)

Supplementary Fig. 5

Stimulation of DOR increases γ-secretase activity in LEL. (PDF 363 kb)

Supplementary Fig. 6

Stimulation of endogenous β2AR increases localization of γ-secretase components in LEL. (PDF 1320 kb)

Supplementary Fig. 7

Association of DOR and PS1 in rat hippocampus. (PDF 389 kb)

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Ni, Y., Zhao, X., Bao, G. et al. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nat Med 12, 1390–1396 (2006). https://doi.org/10.1038/nm1485

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