Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β1-42 deposition

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

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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-β42 (Aβ42) 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 Aβ42 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 Aβ42 accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ42 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 Aβ42 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 Aβ42 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.

Original languageEnglish (US)
Pages (from-to)605-622
Number of pages18
JournalJournal of Alzheimer's Disease
Issue number4
StatePublished - 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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