| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Amyloid beta protein (Abeta) deposition is one of the major pathological hallmarks in Alzheimer's disease (AD) brains.. Abeta is classified into two major subspecies, Abeta40 and Abeta42, and Abeta42 is found to be the initial depositing subspecies which facilitates Abeta deposition in a nucleation depending manner. In vitro Abeta is neuro toxic for cultural neurons, thus it is widely believed that aggregated Abeta causes neuronal dysfunction and loss in AD brains (Abeta cascade theory). Accordingly, discovering reagents which reduce the production of Abeta, especially Abeta42 might be one of the therapeutic objects. However, the intracellular Abeta production compartments which could be the drug target have not been determined.. Thus, our first experimental aim was to clarify the organelles producing Abeta. Using cultural cells and a sensitive Abeta ELISA system, we found that : 1) Abeta4O and Abeta42 are produced in the Golgi apparatus ; 2) some Abeta42 is also created in endoplasmic
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reticulum.
According to the Abeta cascade theory, in vivo neurons should be sensitive to aggregated Abeta. However, no such evidence has been presented so far. Furthermore, recent reports using amyloid precursor protein transgenic mice showed that neuronal loss was not observed even in the presence of numerous Abeta deposition in brains. These results may point out that Abeta deposition is not the cause of cell death but the consequence. To check this possibility, we focused on the effects of cholesterol and sphingolipid metabolism on Abeta production, because the geno- types of cholesterol carrier protein apoE is a major risk factor for AD.We looked at the Abeta production employing a series of drugs which affect the cholesterol and sphigolipid metabolism using K293 cells , but could not get significant effects.. Recently, we found that Abeta and cholesterol share the same special compartment in a neuroblastoma cell line. This finding may suggest that neuronal membrane lipid metabolism effects on Abeta production specifically. Regarding on this notion, now we are continuing some experiments using human materials. Less
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