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.
|Original language||English (US)|
|Number of pages||7|
|State||Published - Dec 2006|
Bibliographical noteFunding Information:
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 b2-AR TYY plasmid; S.L. Schmid (The Scripps Research Institute) for Dyn K44A plasmid; S. Marullo (The Cochin Institute) for b3-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).