A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro.
Fibril formation of amyloid beta peptide (Abeta) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Abeta fibril is formed by a protein misfolding process in which intermolecular beta-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to find compounds which have a profile as a beta-sheet breaker. We searched for a beta-sheet breaker profile in an in-house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine (named RS-0406), which had been newly synthesized in our laboratory. This compound (10-100 microg ml(-1)) was found to be capable of significantly inhibiting 25 microM Abeta(1-42) fibrillogenesis and, furthermore, disassembling preformed Abeta(1-42) fibrils in vitro. 3 We then investigated the effect of RS-0406 on 111 nM Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons, and found that 0.3-3 microg ml(-1) RS-0406 ameliorates the cytotoxicity. Moreover, 3 microg ml(-1) RS-0406 reversed 1 micro M Abeta(1-42)-induced impairment of long-term potentiation in hippocampal slices. 4 In this study, we have succeeded in identifying RS-0406 which has potential to inhibit Abeta(1-42) fibrillogenesis, and to protect neurons against Abeta(1-42)-induced biological toxicity in vitro. These results suggest that RS-0406 or one of the derivatives could become a therapeutic agent for AD patients.
Nakagami
Yasuhiro
Y
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. yasuhiro@shina.sankyo.co.jp
Nishimura
Satoko
S
Murasugi
Takako
T
Kaneko
Isao
I
Meguro
Masaki
M
Marumoto
Shinji
S
Kogen
Hiroshi
H
Koyama
Kazuo
K
Oda
Tomiichiro
T
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D003959:Diamines; C472970:N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine; D010446:Peptide Fragments; D011724:Pyridazines; C075222:amyloid beta-protein (1-42)