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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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).
The authors declare no competing financial interests.
Stimulation of endogenous DOR enhances γ-secretase activity. (PDF 138 kb)
Time course of γ-secretase activity after stimulation of β2AR. (PDF 260 kb)
Pertussis toxin does not affect DOR-induced enhancement of γ-secretase activity. (PDF 221 kb)
Transferrin can not induce γ-secretase activity enhancement. (PDF 230 kb)
Stimulation of DOR increases γ-secretase activity in LEL. (PDF 363 kb)
Stimulation of endogenous β2AR increases localization of γ-secretase components in LEL. (PDF 1320 kb)
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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