2006 Fiscal Year Final Research Report Summary
Research on cerebral beta-amyloid deposition and neurodegeneration related to lipid metabolism of the plasma membrane.
| Project/Area Number |
16300110
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Gunma University |
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Principal Investigator |
YAMAGUCHI Haruyasu Gunma University, School of Health Sciences, Professor, 医学部, 教授 (00158114)
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| Co-Investigator(Kenkyū-buntansha) |
SASAKI Atsushi Gunma University, Graduate School of Medicine, Lecturer, 大学院・医学系研究科, 講師 (80225862)
IWASHITA Yoshiko Tokyo Metropolitan Institute of Gerontology, Biomembrane Research Group, Group leader, 福祉振興財団・都老人研・生体膜機能研究グループ, 副参事研究員 (50111498)
MORI Takashi Saitama Medical Center/School, Associate professor, 医学部, 助教授 (60239605)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Alzheimer's disease / amyloid β protein / lipid raft / cholesterol / apolipoprotein E / dementia |
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| Research Abstract |
To clarify whether rafts are the site of abnormal Aβ deposition, we examined the ultrastructural localization of both flotillin-1 (pre-embedding) and Aβ (post-embedding) in Tg2576 mouse brains and those of the Alzheimer's disease (AD). The number of flotillin-1-positive rafts per field in mature plaques was prominently less than those outside of the plaque, in diffuse plaques and in primitive plaques. The colocalization of flotillin-1 with Aβ42 appeared approximately 10 % of flotillin-1-positive rafts within senile plaques, while there was no colocalization found outside of the plaques. This study ultrastructurally demonstrated that part of membrane-bound Aβ exists in lipid rafts within senile plaques, and suggests that rafts could be one of the sites for initial Aβ deposition.
Soluble Aβ oligomers have recently been considered to be responsible for cognitive dysfunction prior to senile plaque formation in AD brain. To investigate the ultrastructural localization of soluble Aβ oligomers
… More
, we conducted the post-embedding immuno-electron microscopic study using an antibody against a molecular mimic of oligomeric Aβ. Oligomer-specific immunoreactions detected by IEM tended to be found with higher density 1) in AD than in nondemented brains and 2) at the axon and axon terminal in AD than in nondemented brains. These findings imply that soluble Aβ oligomers might be related to synaptic dysfunction in AD brain.
W also found that β-protein degrading enzyme, neprilysin, present synaptic dysfunction in AD by reducing accumulation of Aβ oligoner at the pre-synaptic terminals.
Iwashita examined abnormality of the cell surface lipid raft using the NPC1-deficit CHO cells, and found increased density of the lipid raft on the cell surface membrane.
Mori examined the effect of arundic acid, which is known to negatively regulate astrocyte synthesis of S100B on Aβ deposition in Tg2576 APP Tg mouse brain. Aβ deposits along with amyloid-β peptide/S100B levels, as well as plaque-associated reactive gliosis (astrocytosis and microgliosis), were significantly ameliorated in arundic acid-treated mice. Less
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