2004 Fiscal Year Final Research Report Summary
An investigation into molecular mechanism underlying Aβ assembly
| Project/Area Number |
12210022
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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 | National Institute for Longevity Sciences |
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Principal Investigator |
YANAGISAWA Katsuhiko Natl Inst for Longevity Sci., Dept of Alzheimer's Disease Research, Head, (研究所), 副所長 (10230260)
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| Project Period (FY) |
2000 – 2004
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| Keywords | Alzheimer's disease / amyloid β-protein / ganglioside / apolipoprotein F. / synapse / microdomain / hereditary variant |
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| Research Abstract |
The assembly and deposition of amyloid Β-protein (Aβ) in the brain are the fundamental processes in the development of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). However, it remains to be determined how a nontoxic monomeric Aβ is converted into its toxic assembled form. We previously identified a unique Aβ species, which is characterized by its tight binding to GM1 ganglioside, in the brain with early pathological changes of AD. On the basis of the unique molecular characteristics of GM1 ganglioside-bound Aβ (GAβ), we hypothesized that Aβ adopts an altered conformation through its binding to GM1 ganglioside and acts as a seed for Aβ assembly. In the present study, we investigated into molecular mechanism underlying GAβ generation in the brain. We examined human apolipoprotein E knock-in mice and found that the level of GM1 ganglioside in the membrane microdomains of neuronal membranes, such as detergent-resistant microdomains (DRMs), can be increased with age and by expression of apolipoprotein E4, leading to facilitation of Aβ assembly through GAβ generation. We have also validated the GAβ generation in the brain using a novel monoclonal antibody raised against purified GAβ. Furthermore, we have found that the assembly of hereditary variant forms of Aβ, including the Arctic-, Dutch-, and Flemish-type Aβs, is facilitated in the presence of particular gangliosides, which are selectively expressed at the sites of preferential deposition of these variant Aβs. In conclusion, pivotal role of gangliosides in induction of Aβ assembly and deposition in the AD and CAA brains has been indicated in the present study.
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