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Article
Nature Medicine 12, 1390 - 1396 (2006)
Published online: 19 November 2006 | doi:10.1038/nm1485
Activation of 
2-adrenergic receptor stimulates 
-secretase activity and accelerates amyloid plaque formation
Yanxiang Ni1,3, Xiaohui Zhao1,3, Guobin Bao1, Lin Zou1, Lin Teng1, Zhu Wang1, Min Song2, Jiaxiang Xiong2, Yun Bai2 & Gang Pei1
Abstract
Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the 
-secretase catalytic subunit, can affect amyloid-
(A) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how -secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including 2-adrenergic receptor (2-AR). Here we report that activation of 2-AR enhanced -secretase activity and thus A production. This enhancement involved the association of 2-AR with presenilin-1 and required agonist-induced endocytosis of 2-AR and subsequent trafficking of -secretase to late endosomes and lysosomes, where A production was elevated. Similar effects were observed after activation of 
-opioid receptor. Furthermore, chronic treatment with 2-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, 2-AR activation can stimulate -secretase activity and amyloid plaque formation, which suggests that abnormal activation of 2-AR might contribute to A accumulation in Alzheimer disease pathogenesis.
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