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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO 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 AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO 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 AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)934-947
Number of pages14
JournalJournal of neurochemistry
Volume142
Issue number6
DOIs
StatePublished - Sep 1 2017

Fingerprint

Single-Chain Antibodies
Oligomers
Amyloid
Alzheimer Disease
Molecular Weight
Molecular weight
Brain
Neurons
Immunoglobulin Fragments
Oxidative stress
Molecular mass
Brain Diseases
Dendrites
Dimers
Transgenic Mice
Consensus
Oxidative Stress
Tissue
Peptides
Antibodies

Keywords

  • Alzheimer's disease
  • amyloid β oligomers
  • conformational antibodies
  • scFvs

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Sebollela, Adriano ; Cline, Erika N. ; Popova, Izolda A ; 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. / A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers. In: Journal of neurochemistry. 2017 ; Vol. 142, No. 6. pp. 934-947.
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abstract = "Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO 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 AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO 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 AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. (Figure presented.).",
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author = "Adriano Sebollela and Cline, {Erika N.} and Popova, {Izolda A} and Kevin Luo and Xiaoxia Sun and Jay Ahn and Barcelos, {Milena A.} and Bezerra, {Vanessa N.} and {Lyra e Silva}, {Natalia M.} and Jason Patel and Pinheiro, {Nathalia R.} and Qin, {Lei A.} and Kamel, {Josette M.} and Anthea Weng and Nadia DiNunno and Bebenek, {Adrian M.} and Velasco, {Pauline T.} and Viola, {Kirsten L.} and Lacor, {Pascale N.} and Ferreira, {Sergio T.} and Klein, {William L}",
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Sebollela, A, Cline, EN, Popova, IA, Luo, K, Sun, X, Ahn, J, Barcelos, MA, Bezerra, VN, Lyra e Silva, NM, Patel, J, Pinheiro, NR, Qin, LA, Kamel, JM, Weng, A, DiNunno, N, Bebenek, AM, Velasco, PT, Viola, KL, Lacor, PN, Ferreira, ST & Klein, WL 2017, 'A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers', Journal of neurochemistry, vol. 142, no. 6, pp. 934-947. https://doi.org/10.1111/jnc.14118

A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers. / Sebollela, Adriano; Cline, Erika N.; Popova, Izolda A; 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.

In: Journal of neurochemistry, Vol. 142, No. 6, 01.09.2017, p. 934-947.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers

AU - Sebollela, Adriano

AU - Cline, Erika N.

AU - Popova, Izolda A

AU - Luo, Kevin

AU - Sun, Xiaoxia

AU - Ahn, Jay

AU - Barcelos, Milena A.

AU - Bezerra, Vanessa N.

AU - Lyra e Silva, Natalia M.

AU - Patel, Jason

AU - Pinheiro, Nathalia R.

AU - Qin, Lei A.

AU - Kamel, Josette M.

AU - Weng, Anthea

AU - DiNunno, Nadia

AU - Bebenek, Adrian M.

AU - Velasco, Pauline T.

AU - Viola, Kirsten L.

AU - Lacor, Pascale N.

AU - Ferreira, Sergio T.

AU - Klein, William L

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO 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 AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO 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 AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. (Figure presented.).

AB - Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO 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 AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO 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 AβOs from both monomeric and fibrillar Aβ. NUsc1 readily detected AβOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AβO binding and reduced AβO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AβOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AβOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AβO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. (Figure presented.).

KW - Alzheimer's disease

KW - amyloid β oligomers

KW - conformational antibodies

KW - scFvs

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DO - 10.1111/jnc.14118

M3 - Article

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VL - 142

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EP - 947

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

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