| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
This study confirmed the possibility that the dysfunction of cerebral Amyloid beta pretein (Aβ) degradation system leads to Alzheimer's disease (AD), and then provided a new strategy for overcoming AD. Result : 1 Electrophysological experiment : the hippocampal synaptic transmission function was examined by recording the field excitatory post-synaptic potentials (fEPSP) ; impaired long term potentiation (LTP) was found in CA1 and DG area in both APP transgenic (APP-tg) mice and Neprilysin knock out (KO) APP transgenic (Neprilysin-KO/APP-tg) mice. Compared with APP-tg mice, the impairment of hippocampal LTP in Neprilysin-KO/APP-tg mice was significant stranger. 2, Behavioral experiment : the ability of learning and memory in Neprilysin-KO/APP-tg mice was significant inhibited than that in APP-tg mice. 3, Western blotting indicated that the cerebral soluble Aβ oligomer in Neprilysin-KO/APP-tg mice increased about 3-folds related to that measured in APP-tg mice. 4, immunohistochemical staining indicated that Aβplaque was neither detected in the APP-tg mice nor even in the Neprilysin-KO/APP-tg mice, suggesting that the functional impairment in young Neprilysin-KO/APP-tg mice were not directly caused by formation of Aβplaque.
Conclusion : 1, the function disorder of Aβdegradation system in brain contributes to development of AD. 2, soluble Aβoligomer but not insoluble Aβplaques inhibits synaptic plasticity at an earlier step of Aβaccumulation. 3, this study provides a new idea that increasing the activity of cerebral Aβdegradation mechanism can prevents and overcomes AD. And 4, this study provides a unique mouse model (Neprilysin-KO/APP-tg mice) for the investigation of pathology and pathophysiology of Aβaccumulation : compared with single APP-tg mouse, the concentration of Aβ increase without changes in other APP breakdown products in the brain.
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