A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-beta oligomers

Author(s):Show less -

Sebollela, Adriano ; Cline, Erika N. ; Popova, Izolda ; Luo, Kevin ; Sun, Xiaoxia ; Ahn, Jay ; Barcelos, Milena A. ; Bezerra, Vanessa N. ; Lyra e Silva, Natalia M. ; Patel, Jason ; Pinheiro, Nathalia R. ; Qin, Lei A. ; Kamel, Josette M. ; Weng, Anthea ; DiNunno, Nadia ; Bebenek, Adrian M. ; Velasco, Pauline T. ; Viola, Kirsten L. ; Lacor, Pascale N. ; Ferreira, Sergio T. ; Klein, William L.

• Document type: Journal article
• Source: Journal of Neurochemistry; v. 142, n. 6, p. 934-947, SEP 2017.
• Web of Science Citations: 8

Abstract

Brain accumulation of soluble oligomers of the amyloid-beta peptide (A beta Os) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). Avariety of A beta O species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which A beta O species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AbOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AbO species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish A beta Os from both monomeric and fibrillar A beta. NUsc1 readily detected A beta Ospreviously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AbO binding and reduced A beta O-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenicmice from wild type (WT) mice, and detected endogenous A beta Os in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of A beta Os with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular A beta O species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. (AU)

• FAPESP's process: 14/25681-3 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis
• Grantee: Adriano Silva Sebollela
• Support Opportunities: Research Grants - Young Investigators Grants