Monoclonal antibody against the turn of the 42-residue amyloid β-protein at positions 22 and 23

Kazuma Murakami, Yuko Horikoshi-Sakuraba, Nakaba Murata, Yoshihiro Noda, Yuichi Masuda, Noriaki Kinoshita, Hiroyuki Hatsuta, Shigeo Murayama, Takuji Shirasawa, Takahiko Shimizu, Kazuhiro Irie

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

Aggregation of the 42-mer amyloid β-protein (Aβ42) plays a critical role in the pathogenesis of Alzheimer's disease (AD). We have proposed a toxic conformer with a turn at positions 22 and 23, as well as a nontoxic conformer with a turn at positions 25 and 26, in Aβ42 aggregates from systematic proline scanning and solid-state NMR studies. Although recent clinical trials of immunization targeting Aβ42 aggregates have proved useful, some adverse effects were reported. One of the reasons was hypothesized to be excessive immunoreactions derived from the unintended removal of nontoxic Aβ42, which plays an important role in the physiological function. To develop a monoclonal antibody for toxic Aβ42, E22P-Aβ10-35, a minimum moiety for neurotoxicity containing the turn at positions 22 and 23, was used for the generation of antibodies, following the selection of clones using Aβ42 mutants of E22P (turn-inducing) and E22V (turn-preventing). The obtained clone (11A1) showed a high binding affinity (KD = 10.3 nM) for Aβ42 using surface plasmon resonance. 11A1 also inhibited the neurotoxicity of Aβ42 in PC12 cells. Immunohistochemical studies showed that not only extracellular but intracellular amyloid was stained in human AD brains. In Western blotting analyses using human brains, low-molecular weight-oligomers rather than the monomer of Aβ were readily recognized by 11A1. These results imply that 11A1 could detect toxic Aβ42 oligomers with the turn at positions 22 and 23 and that 11A1 could be applicable for the therapeutic targeting of toxic Aβ42 in AD.

Original languageEnglish
Pages (from-to)747-756
Number of pages10
JournalACS Chemical Neuroscience
Volume1
Issue number11
DOIs
Publication statusPublished - 2010 Nov 17

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Fingerprint Dive into the research topics of 'Monoclonal antibody against the turn of the 42-residue amyloid β-protein at positions 22 and 23'. Together they form a unique fingerprint.

Cite this