Abstract:
Longer lifespan produces risks of age-associated neurodegenerative disorders such as Alzheimer\'s disease (AD), which is characterized by declines in memory and cognitive function. The pathogenic causes of AD are thought to reflect a progressive aggregation in the brain of amyloid plaques composed of beta-amyloid (Aß) peptides and neurofibrillary tangles composed of phosphorylated tau protein. Recently, long-standing investigations of the Aß disease hypothesis gained support via a passive immunotherapy targeting soluble Aß protein. Tau-targeting approaches using antibodies are also being pursued as a therapeutic approach to AD. In genome-wide association studies, the disease modifier gene Bin1 has been identified as a top risk factor for late-onset AD in human populations, with recent studies suggesting that Bin1 binds tau and influences its extracellular deposition. Interestingly, before AD emerges in the brain, tau levels rise in the colon, where Bin1-a modifier of tissue barrier function and inflammation-acts to promote inflammatory bowel disease (IBD). This connection is provocative given clinical evidence of gut-brain communication in age-associated neurodegenerative disorders, including AD. In this review, we discuss a Bin1-targeting passive immunotherapy developed in our laboratory to treat IBD that may offer a strategy to indirectly reduce tau deposition and limit AD onset or progression.
摘要:
更长的寿命会产生与年龄相关的神经退行性疾病的风险,如阿尔茨海默病(AD),其特征是记忆和认知功能下降。AD的致病原因被认为反映了由β-淀粉样蛋白(Aβ)肽组成的淀粉样蛋白斑块和由磷酸化tau蛋白组成的神经原纤维缠结在大脑中的逐渐聚集。最近,通过针对可溶性Aβ蛋白的被动免疫治疗,对Aβ疾病假说的长期研究获得了支持.使用抗体的Tau靶向方法也被追求作为AD的治疗方法。在全基因组关联研究中,疾病修饰基因Bin1已被确定为人群中晚发性AD的最高危险因素,最近的研究表明Bin1结合tau并影响其细胞外沉积。有趣的是,在AD出现在大脑之前,结肠中的tau水平上升,其中Bin1是组织屏障功能和炎症的调节剂,可促进炎症性肠病(IBD)。考虑到与年龄相关的神经退行性疾病中肠-脑通信的临床证据,这种联系具有挑衅性。包括AD。在这次审查中,我们讨论了我们实验室开发的用于治疗IBD的Bin1靶向被动免疫疗法,该疗法可能提供间接减少tau沉积并限制AD发病或进展的策略.