老年斑、神经元纤维缠结与硫酸多糖

老年斑 (senileplaques ,SP)、神经元纤维缠结 (neurofib rillarytangles,NFTs)是老年性痴呆最典型的病理特征 ,其中SP的主要成分为 β样淀粉蛋白 (Aβ) ,NFTs主要由异常修饰的tau蛋白组成。许多研究发现硫酸多糖与SP、NFTs的形成密切相关。大量文献报道硫酸多糖与淀粉样前体蛋白(APP)、Aβ以及tau蛋白具有高度亲和性 ,它不仅可以促进APP的异常代谢 ,导致Aβ的大量产生 ,诱导其形成纤丝并聚集、沉积于细胞外 ,而且还可促进tau蛋白发生高度磷酸化 ,形成成对螺旋丝 (PHF)并聚集成NFTs。但也有文献报道外源性硫酸多糖具有促进APP的神经营养作用 ,抑制Aβ纤丝的形成 ,并增强磷酸酯酶PP2B的活性 ,从而减少tau蛋白的磷酸化修饰。并且硫酸多糖的糖基组成、糖链长度、硫酸基的数目及位置不同 ,它在SP、NFTs的形成过程中扮演的作用也不同 ,所以可通过分子结构改造而使硫酸多糖表现抑制SP、NFTs形成的活性 ,从而达到抗老年性痴呆的作用

The relationships between senile plaques, neurofibrillary tangles and sulfated polysaccharides

Two aberrant structures, extracellular senile plaques (SP) and intracellular neurofibrillary tangles (NFTs) are the characteristic neuropathological hallmarks of Alzheimers disease (AD). Amyloid β protein (Aβ) and hyperphosphorylated tau protein are the major components of SP and NFTs respectively. A large body of evidence has highlighted the pivotal role of sulfated polysaccharides in the amyloidogenesis and formation of NFTs. The underlying mechanisms of the involvement of sulfated polysaccharides in the development of AD were reported to contribute to their high affinity for both Aβ and tau protein. Sulfated polysaccharides not only promoted the β secretase cleavage of APP and the increased production of Aβ and induced the aggregation and deposition of Aβ, but also facilitated the phosphylation of tau and promoted tau polymerization into fibrils and tangle formation. On the other hand, the neurotrophic effects exerted by sulfated polysaccharides were also demonstrated. These notions were probably due to the inhibition of the formation of Aβ fibrils or to the counteraction of the abnormal phosphorylation of tau by promoting the protein phosphatase2B activity, which has been speculated to be attributed to the variation in either structural backbone or degree of sulfation or position of sulfation. Putting together, the appropriate structural modification of sulfated polysaccharides may be effective as therapeutic agents for AD.