title: Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease.
abstract: Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected (125)I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Xian-Le
authors.initials: XL
authors.lastname: Bu
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Shen
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Shu-Sheng
authors.initials: SS
authors.lastname: Jiao
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Song
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China.
authors.forename: Hua-Dong
authors.initials: HD
authors.lastname: Zhou
authors.affiliation: School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, SA, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, China. yanjiang_wang@tmmu.edu.cn.
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007457:Iodine Radioisotopes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Amyloid-beta; Clearance; Kidney; Liver; Parabiosis; Periphery