Epitopes described in "Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition."

Reference
Article Authors:Robert G Nagele; Peter M Clifford; Gilbert Siu; Eli C Levin; Nimish K Acharya; Min Han; Mary C Kosciuk; Venkat Venkataraman; Semah Zavareh; Shabnam Zarrabi; Kristin Kinsler; Nikhil G Thaker; Eric P Nagele; Jacqueline Dash; Hoau Y Wang; Andrew Levitas
Article Title:Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition.
Reference Detail
Reference ID:1022334
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-(42) (A(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 A pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble A(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 A(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal A(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 A(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 A(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.
Affiliations:New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA. nagelero@umdnj.edu
Date:2011
Reference Type:Literature
PubMed ID:21483091
Journal:J Alzheimers Dis
Journal Volume:25
Article Pages:605-22
Journal ISSN:1387-2877
Article Chemical List:Amyloid beta-Peptides;Autoantibodies;Immunoglobulin G;Nerve Tissue Proteins;Peptide Fragments;amyloid beta-protein (1-42)
Article MeSH List:Aged; Aged, 80 and over; Amyloid beta-Peptides(metabolism); Animals; Autoantibodies(blood); Blood-Brain Barrier; Blotting, Western; Brain(immunology); Female; Humans; Image Processing, Computer-Assisted; Immunoglobulin G(metabolism); Immunohistochemistry; Male; Mice; Nerve Tissue Proteins(metabolism); Neurons(metabolism); Organ Culture Techniques; Peptide Fragments(metabolism); Pyramidal Cells(metabolism); Rats; Rats, Sprague-Dawley
Curation Last Updated:2014-07-16 22:51:02