title: α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction.
abstract: Accumulation of amyloid β (Aβ) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aβ generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α(2A) adrenergic receptor (α(2A)AR). Genetic deficiency of the α(2A)AR significantly reduces, whereas stimulation of this receptor enhances, Aβ generation and AD-related pathology. Activation of α(2A)AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α(2A)AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by β secretase. The α(2A)AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α(2A)AR-promoted Aβ generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α(2A)AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α(2A)AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α(2A)R antagonists would be an effective therapeutic strategy for AD.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Yunjia
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Yin
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Pulin
authors.initials: P
authors.lastname: Che
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Mary
authors.initials: M
authors.lastname: Gannon
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Alzheimer's Disease Research Center, Mayo Clinic, Jacksonville, FL 32224; and.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Kai
authors.initials: K
authors.lastname: Jiao
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; qinwang@uab.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: C547769:Adra2a protein, mouse; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026901:Membrane Transport Proteins; D010446:Peptide Fragments; D018341:Receptors, Adrenergic, alpha-2; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; C075222:amyloid beta-protein (1-42)
keywords: SorLA; adrenergic receptor; amyloid; processing; sorting