2004 Fiscal Year Final Research Report Summary
The roles of proteolytic systems in brain aging
| Project/Area Number |
12210019
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | The Physical and Chemical Research, RIKEN |
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Principal Investigator |
SAIDO Takaomi C. RIKEN, Lab. for Proteolytic Neuroscience, Laboratory Head, 神経蛋白制御研究チーム, チームリーダー (80205690)
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| Project Period (FY) |
2000 – 2004
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| Keywords | Alzheimer's disease / β amyloid / neprilysin / calpain / calpastatin / caspase / somatostatin / brain aging |
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| Research Abstract |
First, we analyzed the metabolism of Alzheimer's amyloid β peptide (A β) in the brain and discovered the following; [1] A neutral endopeptidase, neprilysin, is the major A β-degrading enzyme in the brain. [2] Reduction of neprilysin activity results in elevation of Aβ burdens. [3] Expression of neprilysin in the brain decreases upon aging. [4] Expression of neprilysin cDNA using a viral vector in the brain of Aβ amyloidosis mouse model leads to suppression of Aβ deposition. [5] Reduction of neprilysin activity in the brain of A β amyloidosis mouse model results in inhibition of long-term potentiation and in memory-associated behavioral abnormality. [6] A neuropeptide, somatostatin, facilitates A β metabolism through activation of neuronal neprilysn. These findings indicate that modulating brain neprilysin activity using a receptor ligand such as somatostatin receptor agonists may contribute to prevention and treatment of Alzheimer's disease.
Second, we exploited the role of calpain in the neuronal death by generating calpastatin-transgenic and knockout mice, and found the following; [1] In adult brains, calpain, rather than caspses, plays the major role in excitotoxic neuronal cell death. [2] Hyperactivation of calpain in Aβ amyloidosis mouse model augments neuronal degeneration. These observations suggest that calpain is likely to be involved in a broad range of neurodegenerative processes and that inhibitors specific to activated calpain might be effective medications to treat various neurodegenerative processes.
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