Inherent anti-amyloidogenic activity of human immunoglobulin γ heavy chains

Sharad P. Adekar, Igor Klyubin, Sally Macy, Michael J. Rowan, Alan Solomon, Scott K. Dessain, Brian O'Nuallain

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We have previously shown that a subpopulation of naturally occurring human IgGs were cross-reactive against conformational epitopes on pathologic aggregates of Aβ, a peptide that forms amyloid fibrils in the brains of patients with Alzheimer disease, inhibited amyloid fibril growth, and dissociated amyloid in vivo. Here, we describe similar anti-amyloidogenic activity that is a general property of free human Ig γ heavy chains. A γ1 heavy chain, F1, had nanomolar binding to an amyloid fibril-related conformational epitope on synthetic oligomers and fibrils as well as on amyloidladen tissue sections. F1 did not bind to native Aβ monomers, further indicating the conformational nature of its binding site. The inherent anti-amyloidogenic activity of Ig γ heavy chains was demonstrated by nanomolar amyloid fibril and oligomer binding by polyclonal and monoclonal human heavy chains that were isolated from inert or weakly reactive antibodies. Most importantly, the F1 heavy chain prevented in vitro fibril growth and reduced in vivo soluble Aβ oligomer-induced impairment of rodent hippocampal long term potentiation, a cellular mechanism of learning and memory. These findings demonstrate that free human Ig γ heavy chains comprise a novel class of molecules for developing potential therapeutics for Alzheimer disease and other amyloid disorders. Moreover, establishing the molecular basis for heavy chain-amyloidogenic conformer interactions should advance understanding on the types of interactions that these pathologic assemblies have with biological molecules.

Original languageEnglish (US)
Pages (from-to)1066-1074
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - Jan 19 2010

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Immunoglobulin Heavy Chains
Amyloid
Human Activities
Oligomers
Epitopes
Alzheimer Disease
Molecules
Long-Term Potentiation
Growth
Rodentia
Brain
Monomers
Binding Sites
Learning
Tissue
Data storage equipment
Peptides
Antibodies

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Adekar, S. P., Klyubin, I., Macy, S., Rowan, M. J., Solomon, A., Dessain, S. K., & O'Nuallain, B. (2010). Inherent anti-amyloidogenic activity of human immunoglobulin γ heavy chains. Journal of Biological Chemistry, 285(2), 1066-1074. https://doi.org/10.1074/jbc.M109.044321

Inherent anti-amyloidogenic activity of human immunoglobulin γ heavy chains. / Adekar, Sharad P.; Klyubin, Igor; Macy, Sally; Rowan, Michael J.; Solomon, Alan; Dessain, Scott K.; O'Nuallain, Brian.

In: Journal of Biological Chemistry, Vol. 285, No. 2, 19.01.2010, p. 1066-1074.

Research output: Contribution to journalArticle

Adekar, SP, Klyubin, I, Macy, S, Rowan, MJ, Solomon, A, Dessain, SK & O'Nuallain, B 2010, 'Inherent anti-amyloidogenic activity of human immunoglobulin γ heavy chains', Journal of Biological Chemistry, vol. 285, no. 2, pp. 1066-1074. https://doi.org/10.1074/jbc.M109.044321
Adekar, Sharad P. ; Klyubin, Igor ; Macy, Sally ; Rowan, Michael J. ; Solomon, Alan ; Dessain, Scott K. ; O'Nuallain, Brian. / Inherent anti-amyloidogenic activity of human immunoglobulin γ heavy chains. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 2. pp. 1066-1074.
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