| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
Increasing evidence implicates oxidative stress and mitochondrial abnormalities in the pathogenesis of Alzheimer's disease(AD), which potentially cause apoptotic cell death. While the alterations in the metabolism of β-amyloid are considered to play major roles in AD, the relationship between intraneuronal β-amyloid accumulation and apoptotic signals remains to be elucidated.
We used an in situ approach to identify intraneuronal β-amyloid accumulation, oxidalive damage, and apoptoltc signals in the hippocampus, papahippocampal gyrus and occipitoteraporal gyrus of postmortem brains of AD cases(n=10,age 60-87y). Immunocytochemically, up-stream signals in the apoptotic cascade, mitogen-activated protein kinases such as ERK,JNK/SAPK, and p38 were identified in the pyramidal neurons of these brain regions. Among subsequent signals, initiator caspases(caspases 8 and 9) appeared also in the pyramidal neurons. However, we failed to observe down-stream signals, effecter caspases(caspases 3,6,and 7), which might appear immediately before apoptotic cell death. Intraneuronal β-amyloid accumulation identified with an antibody against C-terminus of β-amyloid 1-42 showed more widespread distribution compared to any apoptotic signals investigated. Furthermore, oxidative damage to neuronal RNA identified with an antibody against oxidized nucleoside, 8-hydroxyguanosine showed more widespread distribution compared to the intraneuronal β-amyloid accumulation.
These observations suggest temporal primacy of oxidative damage to intraneuronal β-amyloid accumulation and subsequent aclivation of apoptotic signals. The lack of signals of effecter caspases may indicate an abortive process of apoptosis in surviving neurons of AD.
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