title: Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition.
abstract: Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.
authors.affiliation: New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA. nagelero@umdnj.edu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nagele
authors.forename: Peter M
authors.initials: PM
authors.lastname: Clifford
authors.forename: Gilbert
authors.initials: G
authors.lastname: Siu
authors.forename: Eli C
authors.initials: EC
authors.lastname: Levin
authors.forename: Nimish K
authors.initials: NK
authors.lastname: Acharya
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.forename: Mary C
authors.initials: MC
authors.lastname: Kosciuk
authors.forename: Venkat
authors.initials: V
authors.lastname: Venkataraman
authors.forename: Semah
authors.initials: S
authors.lastname: Zavareh
authors.forename: Shabnam
authors.initials: S
authors.lastname: Zarrabi
authors.forename: Kristin
authors.initials: K
authors.lastname: Kinsler
authors.forename: Nikhil G
authors.initials: NG
authors.lastname: Thaker
authors.forename: Eric P
authors.initials: EP
authors.lastname: Nagele
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dash
authors.forename: Hoau Y
authors.initials: HY
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Levitas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001921:Brain / Q000276:immunology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D001323:Autoantibodies; D007074:Immunoglobulin G; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)