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

为了明确筏是否为Aβ异常沉积的部位，我们检测了Tg2576小鼠和阿尔茨海默病（AD）小鼠大脑中flotilin -1（包埋前）和Aβ（包埋后）的超微结构定位。成熟斑块中每野flotilin -1阳性筏的数量明显少于斑块外、弥漫性斑块和原始斑块。flotilin -1与Aβ42共定位出现在老年斑内约10%的flotilin -1阳性筏，而斑块外未发现共定位。本研究在超微结构上证实老年斑内脂筏中存在部分膜结合的Aβ，提示脂筏可能是Aβ初始沉积的部位之一。可溶性Aβ低聚物最近被认为是AD大脑中老年斑形成之前的认知功能障碍的原因。为了研究可溶性a β低聚物的超微结构定位，我们利用抗体对a β低聚物分子模拟物进行了包埋后免疫电镜研究。IEM检测到的寡聚物特异性免疫反应密度倾向于：(1)阿尔茨海默氏症患者比非痴呆症患者高，(2)阿尔茨海默氏症患者轴突和轴突末端比非痴呆症患者高。这些发现提示可溶性Aβ低聚物可能与AD脑突触功能障碍有关。W还发现β蛋白降解酶neprilysin通过减少突触前末端Aβ寡聚物的积累，在AD中出现突触功能障碍。Iwashita使用npc1缺陷的CHO细胞检查细胞表面脂筏的异常情况，发现细胞膜表面脂筏密度增加。Mori检测了环己酸对Tg2576 APP Tg小鼠脑内Aβ沉积的影响，环己酸已知可负调控S100B星形胶质细胞合成。Aβ沉积、淀粉样蛋白-β肽/S100B水平以及斑块相关的反应性胶质细胞增生（星形细胞增生和小胶质细胞增生）在环戊二酸处理的小鼠中得到显著改善。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