老年痴呆实验动物型研制进展.ppt

NFM 17026 RW Tau 蛋 白 的 轴 突 转 运 障碍 方法：免疫沉淀 (IP), 免疫电泳 N-Tg: 正常非 转基因小鼠 hWT: 正常 Tau 转基因小鼠 RW: RW Tau 变异转基因小鼠 中 分子量神 经丝抗体 Tau 旦白 抗体 脊髓腹根结扎 Since abnormal PHF tau proteins could not perform the normal function of binding to and stabilizing microtubules (MTs) in the polymerized state, could further effect MT functions, especially fast axonal transport. The hypothesis: MT stabilizing drugs such as Paxceed TM delivering to the CNS could have therapeutic benefit in brains with tauopathies 假说 Hypothesis ? Taxol R (Paclitaxel, mw 854) -isolated in 1971 from plant, the pacific yew Taxus brevifonia -the first of a class of MT stabilizing drug which was approved for use in the treatment of breast, ovarian and lung cancers; -appears to arrest cells in mitosis by stabilizing spindle MTs. - induce MT polymer mass in cell and “MT bundling”; -readily soluble in methanol, but limited soluble in water; ? Paxceed TM -A new MT Stabilizing anti-neoplastic agent by Angiotech Inc. ; -In contrast to Taxol ( Cremaphor formulation) , Paxceed TM is a Micellar formulation that does not cause the inflammatory reactions; -Micellar paclitaxel is soluble in saline and once in the bloodstream, the micelles break down so that the paclitaxel can bind to serum albumin for bioavailability. 微管稳定药物 MT Stabilizing Drugs -Over express the shortest tau isoform (T44) with mouse PrP promotor; Tau inclusions begin to accumulate in spinal cord of 9 month old T44 tau Tg mice in association with the onset of motor impairments. Neuron, Ishihara et al., 1999 T44 Tau Tg mice NFTs accumulate with age in cortical neurons of T44 tau Tg mice. Pre-embedding immuno-EM shows tau immunoreactive straight filaments in cortical NFTs of a 24 month old T44 tau Tg mouse. AJP , Ishihara et al., 2001 T44 Tau Tg mice - Retardation of fast a