AGING AND ALZHEIMER DEMENTIA--ROLE OF FIBROUS PROTEIN

这个项目的长期目标是了解生物学和 阿尔茨海默病的分子发病机制--最常见的器质性疾病 老年痴呆症。广告的特点是出现了 主要由成对的螺旋细丝组成的神经原纤维缠结 (PHF)。PHF制剂含有tau命名表位的异常形式，但 与抗tau单抗(Tau-1)的反应性不同 牛tau基因外显子2编码区域的抗体 用磷酸酶预处理PHF-tau可提高其与这些蛋白的结合 抗体，提示PHF-tau与正常tau在部位/或 磷酸化的程度。我们最近已经表明，PHF-tau也 在分子质量和等电荷量上不同于正常的tau。 去磷酸化对其生化性质的影响很小。 PHF tau，建议翻译后修饰，除了 磷酸化和/或替代的基因剪接在 PHF-tau的形成。PHF-tau是否除了 上面提到的两个区域包含其他异常区域，如果 磷酸化是唯一区别于 PHF-tau来源于正常tau。也不清楚PHF-tau是否含有额外的 如果PHF-tau的异常磷酸化是 在正常大脑或仅在阿尔茨海默病大脑中，通过蛋白激酶(S)催化。 这些问题将通过比较phf-tau和tau蛋白来回答。 从正常和阿尔茨海默病患者的脑组织中检测其磷含量、氨基酸 作文和序列，翻译后修饰，通过研究 去磷酸化的PHF-tau与已知的激酶和 脑匀浆中的酪氨酸酶。亚毒性水平的谷氨酸或钙 最近发现离子载体A23187改变了tau的免疫反应性。 培养的神经元。目前还不清楚这一变化是否与那一变化相似 在PHF-Tau。我们的最后一个具体目标是研究这些 对tau的生化和免疫细胞化学性质的处理，以及 对受影响神经元的超微结构的影响。

The long-term goal of this project is the understanding of the biology and molecular pathogenesis of Alzheimer's disease (AD), the most common organic dementia seen in old age. AD is characterized by the presence of neurofibrillary tangles which consist primarily of paired helical filaments (PHF). PHF preparations contain aberrant forms of tau named epitopes but differed in reactivity with a monoclonal anti-tau antibody (Tau-1) and antibodies to a region of bovine tau encoded by tau gene exon 2. A pretreatment of PHF-tau with phosphatase improved its binding with these antibodies, suggesting that PHF-tau differed from normal tau in the site/or the extent of phosphorylation. We have shown recently that PHF-tau also differed from normal tau in molecular mass and isoelectric charge. Dephosphorylation had very little effect on the biochemical properties of PHF tau, suggesting that post-translational modifications, besides phosphorylation, and/or alternative gene splicing play a role in the formation of PHF-tau. It remains to be determined if PHF-tau, besides the two regions mentioned above, contain other aberrant regions, and if phosphorylation is the only biochemical modification that distinguishes PHF-tau from normal tau. It is also unknown if PHF-tau contains additional phosphorylation sites and if the aberrant phosphorylation of PHF-tau is catalyzed via a protein kinase (s) in normal brains or only in AD brains. These questions will be answered by comparing PHF-tau, and tau proteins from normal and AD brains for their phosphate content, amino acid composition and sequences, post-translational modifications and by studying the rephosphorylation of dephosphorylated PHF-tau with known kinases and kinases from brain homogenates. A subtoxic level of glutamate or calcium ionophore A23187 was recently shown to alter the immunoreactivity of tau in cultured neurons. It is unclear whether this alteration is similar to that in PHF-tau. Our last specific aim is to study the effect of these treatments on the biochemical and immunocytochemical properties of tau, and on the ultrastructure of the affected neurons.