|Budget Amount *help
¥2,700,000 (Direct Cost : ¥2,700,000)
Fiscal Year 1999 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1998 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Neuronal cell death is the central abnormality in Alzheimer's disease (AD). To establish curative therapy for AD, controlling neuronal cell death is mandatory. An important clue is to find the molecules that suppress neuronal cell death by familial AD (FAD) genes mutant APP, PS1 and PS2 and Aβ amyloid. During 1998 and 1999, when I performed this project, little was concluded. However, a great deal of discoveries have been subsequently accomplished by my colleagues at Department of Pharmacology in KEIO University School of Medicine. I established virtually all grounds for these epoch-making discoveries. Followings are the discoveries derived by this project.  Molecular analysis of the neurotoxic mechanisms by various FAD genes and Aβ. It was discovered that different kinds of FAD genes cause neuronal cell death through different combinations of multiple toxic mechanisms, and that each FAD gene triggers different specific cell death mechanisms in a expression level-dependent manner.  Establishment of neuronal cell lines expressing inducible FAD genes.  identification of the novel factor abolishing neuronal cell death by all known kinds of FAD genes and Aβ. Through original disease-based death trap screening, we identified a novel gene, designated Humanin (HN) cDNA, which encodes a secretory 24-residue polypeptide. HN abolished death of neuronal cells by all known kinds of FAD genes and Aβ1-43 without effect on neuronal cell death by Huntington's disease/spinocerebellar ataxia-linked polyglutamine or amyotrophic lateral sclerosis-causative SOD1 mutants. Therefore, HN is a selective and omnipotent suppressor of neuronal cell death caused by AD-relevant insults. The rescue action of HN was mediated by suppression of both Aβ-independent and -dependent neurotoxicities of FAD genes without any effect on Aβ production, suggesting that HN antagonizes against AD-relevant insults in a manner totally supplemental with Aβ-production inhibitors.