title: Estrogen receptor α promotes non-amyloidogenic processing of platelet amyloid precursor protein via the MAPK/ERK pathway.
abstract: Deposition of amyloid β peptide (Aβ), a proteolytic product of amyloid precursor protein (APP), in senile plaques and in the walls of cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Platelets contain high levels of APP and Aβ and may contribute to amyloid deposits seen in AD. However, the biochemical mechanism(s) involved in the regulation of platelet APP metabolism are largely unknown. The estrogen receptor α (ERα) is found to be expressed in platelets. It has not been elucidated whether ERα-mediated non-genomic signaling intervenes with platelet APP processing. Using ERα knock-out (α-ERKO) mice and wild type (WT) littermates, the present study demonstrated that ERα-specific agonist propylpyrazole triol (PPT) promoted non-amyloidogenic processing of platelet APP via the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathway. The underlying basis involves direct association of activated ERK with a disintegrin and metalloprotease domain 17 (ADAM17, an α-secretase candidate) and ERK-dependent threonine phosphorylation of ADAM17. These results suggest that selective modulation of ERα in peripheral target tissues may serve as an anti-amyloidogenic strategy for AD and other amyloidogenic diseases.
authors.affiliation: Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 510182, China. Electronic address: sallyshi431@126.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Shi
authors.affiliation: Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: XiaoMing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
authors.forename: Dahong
authors.initials: D
authors.lastname: Long
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010636:Phenols; D011720:Pyrazoles / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047628:Estrogen Receptor alpha; D010636:Phenols; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Alzheimer’s disease; Amyloid β protein; Estrogen receptor α; Platelet