| RRC ID |
10767
|
| 著者 |
Murakami K, Horikoshi-Sakuraba Y, Murata N, Noda Y, Masuda Y, Kinoshita N, Hatsuta H, Murayama S, Shirasawa T, Shimizu T, Irie K.
|
| タイトル |
Monoclonal antibody against the turn of the 42-residue amyloid β-protein at positions 22 and 23.
|
| ジャーナル |
ACS Chem Neurosci
|
| 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 (K(D) = 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.
|
| 巻・号 |
1(11)
|
| ページ |
747-56
|
| 公開日 |
2010-11-17
|
| DOI |
10.1021/cn100072e
|
| PMID |
22778811
|
| PMC |
PMC3368655
|
| MeSH |
Aged
Aged, 80 and over
Amino Acid Sequence
Amino Acids / chemistry
Amyloid beta-Peptides / drug effects*
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / toxicity*
Animals
Antibodies, Monoclonal / pharmacology*
Blotting, Western
Brain Chemistry / drug effects
Cell Survival / drug effects
Female
Humans
Immunoenzyme Techniques
Immunohistochemistry
In Vitro Techniques
Kinetics
Male
Molecular Sequence Data
Molecular Weight
PC12 Cells
Protein Conformation
Rats
Surface Plasmon Resonance
|
| IF |
4.486
|
| 引用数 |
34
|
|
WOS 分野
|
CHEMISTRY, MEDICINAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
NEUROSCIENCES
|
| リソース情報 |
| ヒト・動物細胞 |
PC-12(RCB0009) |
