title: Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation.
abstract: Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Ni
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.forename: Guobin
authors.initials: G
authors.lastname: Bao
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: Lin
authors.initials: L
authors.lastname: Teng
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Xiong
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004705:Endocytosis; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides; C449186:PS1 antigen; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases