| Co-Investigator(Kenkyū-buntansha) |
KIMURA Koichi Hokkaido Institute of Technology, Bioscience, Associate Professor, 工学部, 助教授 (90177915)
TSUZUKI Kayo Sapporo Medical University, Microbiology, Instructor, 医学部, 助手 (60207420)
|
|---|
| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥6,600,000 (Direct Cost: ¥6,600,000)
|
|---|
| Research Abstract |
Alzheimer's disease (AD) is the most common but complex and heterogenous genetic disorders of dementia. Neuropathology of brains affected with complex and heterogenous disorders of AD shows rather a homogenous feature. This inevitable fact simply indicates that accumulation and aggregation of Amyloid β(Aβ) is the primary cause of AD. Aβ is an about 40 amino acid residue peptide, derived, by two sequential cleavages, from APP. The proteases involved are β-secretase, as the novel aspartyl protease, beta-site APP cleaving enzyme (BACE), and γ-secretase, a multimeric complex containing the presenilins. It is quite reasonable that the balance between the generation and the degradation/clearance of Aβ might be altered in the brains affected with AD. Aβis a about 40 amino acid residue peptide, derived, by two sequential cleavages, from amyloid precursor protein (APP). The proteases involved are β-secretase, as the novel aspartyl protease, (BACE), and γ-secretase, a multimeric complex containing the presenillins.
On the other hand, recently we have established an excellent experimental culture myocyte system under the presence or the absence of chloroquine (CQN) to study APP processing to generate Aβ. In this experiment, we have examined the balance between the generation and the degradation/clearance of Aβ. It is shown that BACE mRNA expression is up-regulated, and Aβ amount is increased under CQN treatment, and that antisense oligonucleotides for BACE treatments reduce the level of C99, β-secretase cleaved C-terminus APP fragment and Aβ level. The inhibition of β-secretase activity might have great therapeutic potential in AD treatment.
|
