Research on cerebral beta-amyloid deposition and neurodegeneration related to lipid metabolism of the plasma membrane.

为了阐明木筏是否是Aβ异常沉积的部位，我们检测了Flotillin-1(包埋前)和Aβ(包埋后)在Tg2576小鼠和阿尔茨海默病(AD)小鼠脑中的超微结构定位。成熟期斑块的Flotillin-1阳性斑块数明显少于斑块外、弥漫性斑块和原始斑块。在老年斑块内，Flotillin-1与Aβ42的共定位出现约10%的Flotillin-1阳性树枝，而斑块外未发现共定位。本研究在超微结构上证实了部分膜结合型A-β存在于老年斑块内的脂筏中，提示脂筏可能是A-β沉积的起始部位之一。近年来，人们认为可溶A-β寡聚体与AD脑内老年斑形成前的认知功能障碍有关。可溶性A-β寡聚体…的超微结构定位研究此外，我们使用了一种针对寡聚体Aβ分子模拟物的抗体进行了包埋后的免疫电子显微镜研究。IEM检测的寡聚体特异性免疫反应密度1)AD组高于非痴呆组，2)AD组轴突和轴突终末高于非痴呆组。这些发现暗示可溶性Aβ寡聚体可能与AD脑内突触功能障碍有关。W还发现β蛋白降解酶Neprilysin通过减少突触前终末Aβ寡聚体的积聚而呈现突触功能障碍。岩下使用NPC1缺失的CHO细胞检测了细胞表面脂筏的异常，发现细胞表膜上的脂筏密度增加。森喜朗研究了花生酸对Tg2576 APP TG小鼠脑内星形胶质细胞合成S100B的负面调节Aβ沉积的影响。Aβ沉积和淀粉样蛋白β肽/S100B水平，以及斑块相关的反应性胶质增生(星形细胞增多症和小胶质细胞增生症)，在接受阿龙酸治疗的小鼠中显著改善。较少

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