阿尔茨海默病新型免疫治疗方法
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摘要
阿尔茨海默病为世界范围内的痴呆常见类型,是目前全球关注的健康热点问题。针对β-淀粉样蛋白(Aβ)沉积和过度磷酸化tau蛋白聚集的内在生物化学机制已有深入研究,来源于正常可溶性Aβ肽的Aβ寡聚体被认为最具毒性。然而,纤维状Aβ聚集形成淀粉样斑块和淀粉样脑血管病是阿尔茨海默病的主要病理改变;而异常磷酸化tau蛋白沉积并形成可溶性毒性寡聚体,进而聚集成为神经原纤维缠结,则是其另一重要病理特征。目前,已有许多措施用于抑制、清除或减缓阿尔茨海默病淀粉样斑块的病理进程,而免疫治疗是这一领域中的新的突破。针对Aβ沉积阿尔茨海默病动物模型进行的主动和被动免疫治疗,已取得重大研究成果。然而,临床试验仅有极少数据显示出明确的疗效,究其原因在于免疫治疗引起的并发症。主动免疫实验引起的脑炎,以及被动免疫治疗在少数人群中诱发的血管源性水肿或淀粉样蛋白相关显像异常已有相关报道。迄今为止,单纯针对tau蛋白聚集的治疗仍然仅局限于小鼠模型,鲜有研究同时针对Aβ沉积和tau蛋白聚集两种病理特征。到目前为止,大部分免疫治疗均以自身蛋白为靶向,尽管其构造异常,在取得疗效的同时,需防止引起过度毒性炎症反应的可能。为取得更好的疗效,未来的免疫治疗应集中在毒性寡聚体,并以阿尔茨海默病的所有病理特征为靶向。
Alzheimer's disease(AD), the most prevalent form of dementia worldwide, can be deemed as the next global health epidemic. The biochemistry underlying deposition of amyloid beta(Aβ) and hyperphosphorylated tau aggregates in AD has been extensively studied.The oligomeric forms of Aβ that are derived from the normal soluble Aβpeptides are believed to be the most toxic. However, it is the fibrillar Aβform that aggregates as amyloid plaques and cerebral amyloid angiopathy, which serve as pathological hallmarks of AD. Moreover,deposits of abnormally phosphorylated tau that form soluble toxic oligomers and then accumulate as neurofibrillary tangles are an essential part of AD pathology. Currently, many strategies are being tested that either inhibit, eradicate or prevent the development of plaques in AD.An exciting new approach on the horizon is the immunization approach.Dramatic results from AD animal models have shown promise for active and passive immune therapies targeting Aβ. However, there is very limited data in humans that suggests a clear benefit. Some hurdles faced with these studies arise from complications noted with therapy.Encephalitis has been reported in trials of active immunization and vasogenic edema or amyloid- related imaging abnormalities(ARIA) has been reported with passive immunization in a minority of patients. As yet, therapies targeting only tau are still limited to mouse models with few studies targeting both pathologies. As the majority of approaches tried so far are based on targeting a selferapy need to-protein, though in an abnormal conformation, benefits of thbe balanced against the possible risks of stimulating excessive toxic inflammation. For better efficacy,future strategies will need to focus on the toxic oligomers and targeting all aspects of AD pathology.
Alzheimer's disease(AD), the most prevalent form of dementia worldwide, can be deemed as the next global health epidemic. The biochemistry underlying deposition of amyloid beta(Aβ) and hyperphosphorylated tau aggregates in AD has been extensively studied.The oligomeric forms of Aβ that are derived from the normal soluble Aβpeptides are believed to be the most toxic. However, it is the fibrillar Aβform that aggregates as amyloid plaques and cerebral amyloid angiopathy, which serve as pathological hallmarks of AD. Moreover,deposits of abnormally phosphorylated tau that form soluble toxic oligomers and then accumulate as neurofibrillary tangles are an essential part of AD pathology. Currently, many strategies are being tested that either inhibit, eradicate or prevent the development of plaques in AD.An exciting new approach on the horizon is the immunization approach.Dramatic results from AD animal models have shown promise for active and passive immune therapies targeting Aβ. However, there is very limited data in humans that suggests a clear benefit. Some hurdles faced with these studies arise from complications noted with therapy.Encephalitis has been reported in trials of active immunization and vasogenic edema or amyloid- related imaging abnormalities(ARIA) has been reported with passive immunization in a minority of patients. As yet, therapies targeting only tau are still limited to mouse models with few studies targeting both pathologies. As the majority of approaches tried so far are based on targeting a selferapy need to-protein, though in an abnormal conformation, benefits of thbe balanced against the possible risks of stimulating excessive toxic inflammation. For better efficacy,future strategies will need to focus on the toxic oligomers and targeting all aspects of AD pathology.
引文
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