免疫治疗阿尔茨海默病的研究进展

摘要

Alzheimer's disease (AD) is a kind of inevitable fatal degenerative disease of the central nervous system, mainly characterized by progressive memory disorders and intelligent recession in clinic. At present, the exact mechanisms leading to the AD are largely remained unknown. The principal neuropathological hallmarks of AD are considered as the extracellular beta-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. At present, the treatment of AD is mainly performed with some drugs, such as acetylcholinesterase (AChE) inhibitor, anti-inflammatory and antioxidant drugs to temporarily alleviate cognitive function in patients. Since Schenk, etc. significantly reduced the Aβdeposits in brains of PDAPP transgenic mice by using Aβ1-42 in 1999, a large number of active and passive immunity treatment of AD animal models have been reported. In 2000, the UK initiated clinical trials (AN1792), AD patients were injected with Aβ1-42, supplemented by adjuvant QS-21. However, phase Ⅱ clinical trial was forced to be halted due to the development of meningoencephalitis in 6% of the patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) then have been developed for clinic trial, but none was observed sufficient effect. In recent years, many improved immunotherapy strategy for AD have been reported, such as the development of DNA vaccines, replacing the adjuvant and immunization route, etc. This review will focus on the research advance in pathogenesis, immunotherapy, and so on.%阿尔茨海默病（Alzheimer disease，AD）是一种进行性的中枢神经系统退行性疾病，其以进行性记忆障碍和智能衰退为主要临床特征。目前关于 AD 的疾病机制尚不清楚，它的发生主要与两种病理改变有关：Aβ的沉积产生蛋白斑（SP）和tau蛋白变性引起神经纤维缠结（NFT）。目前AD的治疗主要是应用乙酰胆碱酯酶（AChE）抑制剂及抗免疫炎性、抗氧化剂等对症治疗药物来暂时缓解患者认知功能减退。自1999年，Schenk等用β淀粉样蛋白1-42（Aβ1-42）免疫PDAPP转基因小鼠并显著地减少小鼠大脑β淀粉样蛋白（Aβ）沉积以来，大量有关主动和被动免疫治疗AD的报道应运而生；2000年，英国首次进行了临床试验（AN1792），但由于6%的患者发生了脑膜脑炎，二期临床试阶段被迫中止。后来关于anti-Aβ单克隆抗体也进行了临床试验，如Bapineuzumab，Solanezumab，但都未观察到理想的治疗效果。近年来许多改良免疫手段治疗AD的报道相继问世，如研制DNA疫苗，更换佐剂和免疫途径等。本文主要就AD的病理机制及其免疫治疗研究进展进行综述。