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

为了阐明筏是否是异常Aβ沉积的位点，我们检查了Flotillin-1（包埋前）和Aβ（包埋后）在Tg 2576小鼠脑和阿尔茨海默病（AD）小鼠脑中的超微结构定位。在成熟斑块中，每个视野中的flotillin-1阳性筏的数量明显少于斑块外、弥漫性斑块和原始斑块。Flotillin-1与Aβ42的共定位出现在老年斑内约10%的Flotillin-1阳性筏中，而在斑块外未发现共定位。本研究从超微结构上证实了部分膜结合Aβ存在于老年斑内的脂筏中，脂筏可能是Aβ沉积的起始部位之一，可溶性Aβ寡聚体最近被认为是AD脑内老年斑形成前认知功能障碍的原因。研究可溶性Aβ寡聚体的超微结构定位 ...更多信息 我们使用抗寡聚体Aβ分子模拟物的抗体进行包埋后免疫电镜研究。IEM检测到的寡聚体特异性免疫反应倾向于发现更高的密度1）在AD比在非痴呆的大脑和2）在轴突和轴突终末AD比在非痴呆的大脑。这些结果表明可溶性Aβ寡聚体可能与AD脑内突触功能障碍有关。W还发现β蛋白降解酶脑啡肽酶通过减少Aβ寡聚体在突触前末梢的积聚而呈现AD的突触功能障碍。Iwashita使用NPC 1缺陷的CHO细胞检测细胞表面脂筏的异常，Mori检查了Arundic酸的作用，已知Arundic酸负调节Tg 2576 APP Tg小鼠脑中星形胶质细胞合成S100 B对Aβ沉积的影响。在阿龙地酸处理的小鼠中，Aβ沉积沿着淀粉样β肽/S100 B水平，以及斑块相关反应性神经胶质增生（星形细胞增生和小神经胶质增生）显著改善。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