title: Autoreactive-Aβ antibodies promote APP β-secretase processing.
abstract: Several prior investigations of Alzheimer's disease (AD) patients have indicated naturally occurring autoantibodies against amyloid-β (Aβ) species are produced. Although many studies have focused on the relative concentrations or binding affinities of autoantibodies against Aβ-related proteins in AD and aging, data regarding their functional properties are limited. It is generally believed that these antibodies act to aid in clearance of Aβ. However, as antibodies which bind to Aβ also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain Aβ-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring Aβ-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote β-secretase activity in cultured cells. Furthermore, using monoclonal antibodies to various regions of Aβ, we found that antibodies generated against the N-terminal region, especially Aβ(1-17) , dose dependently promoted amyloidogenic processing of APP viaβ-secretase activation. Thus, this property of certain autoantibodies in driving Aβ generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-Aβ immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of Aβ, as co-binding to the corresponding region of APP may actually enhance Aβ generation.
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Deng
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Fernandez
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Wataru
authors.initials: W
authors.lastname: Araki
authors.forename: Demian
authors.initials: D
authors.lastname: Obregon
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000276:immunology*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008875:Middle Aged
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001323:Autoantibodies; D053829:Amyloid Precursor Protein Secretases