Research Report
Brain-reactive autoantibodies are nearly ubiquitous in human
sera and may be linked to pathology in the context of
blood–brain barrier breakdown
Eli C. Levin
a,b
, Nimish K. Acharya
b
, Min Han
b
, Semah B. Zavareh
b
, Jonathan C. Sedeyn
b
,
Venkateswar Venkataraman
c
, Robert G. Nagele
a,
⁎
a
New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, 2 Medical Center Drive, Stratford, New Jersey 08084, USA
b
Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, 2 Medical Center Drive, Stratford, New Jersey 08084, USA
c
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, 2 Medical Center Drive, Stratford, New Jersey 08084, USA
ARTICLE INFO ABSTRACT
Article history:
Accepted 14 May 2010
Available online 11 June 2010
Previous studies have reported antibodies bound to cells in postmortem Alzheimer's disease
(AD) brains, which are only rarely observed in thebrainsof healthy,age-matched controls. This
implies that brain-reactive autoantibodies exist in the sera of AD individuals and can gain
access to the brain interstitium. To investigate this possibility, we determined the prevalence
of brain-reactive antibodies in sera from AD patients, patients with other neurodegenerative
diseases, age-matched, non-demented controls and healthy younger individuals via
immunohistochemistry and western blot analysis. Surprisingly, western analyses revealed
that 92% of all human sera tested contain brain-reactive autoantibodies. When sera were used
to probe western blots of human,pig, or rat brain membrane proteins, a number of comparably-
sized protein targets were detected, suggesting cross-species reactivity. While the presence of
brain-reactive autoantibodies was nearly ubiquitous in human sera, some autoantibodies
appeared to be associated with age or disease. Furthermore, the intensity of antibody binding to
brain tissueelements, especially thesurfaces of neurons, correlatedmoreclosely to theserum's
autoantibody profile than to age or the presence of neurodegenerative disease. However, while
the blood–brain barrier(BBB) in control brains remained intact, BBB breakdown was common in
AD brains. Results suggest a high prevalence of brain-reactive antibodies in human sera which,
in the common context of BBB compromise, leads us to propose that these antibodies may
contribute to the initiation and/or pathogenesis of AD and other neurodegenerative diseases.
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Antibody
Autoimmunity
Alzheimer's disease
Neurodegenerative disease
Blood–brain barrier
Serum
1. Introduction
Autoantibodies, components of the immune system with
specificity to self-antigens, can be detected in sera and may
contribute to a host of diseases. In fact, as reviewed by
Diamond et al. (2009), serum autoantibodies have been
implicated in a wide variety of neurological diseases and
syndromes. Neuron-binding autoantibodies have been
detected in sera from individuals exhibiting obsessive com-
pulsive disorder, Sydenham's chorea, pediatric autoimmune
BR AIN R ESEARC H 1345 (2010) 221– 232
⁎ Corresponding author. University of Medicine and Dentistry of New Jersey/SOM, New Jersey Institute for Successful Aging, 2 Medical
Center Drive, room 314, Stratford, NJ 08084, USA. Fax: +1 419 791 3345.
E-mail address: nagelero@umdnj.edu (R.G. Nagele).
0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2010.05.038
available at www.sciencedirect.com
www.elsevier.com/locate/brainres