Department of Geriatrics, Center for Aging Brain, University of Bari Policlinico, Piazza Giulio Cesare, 11 - 70124 Bari - Italy.
Curr Alzheimer Res. 2010 Feb;7(1):40-55. doi: 10.2174/156720510790274400.
Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of beta-amyloid (Abeta) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Abeta have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, beta-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of gamma-secretase, the protease that regulates the last metabolic step generating Abeta, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Abeta aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Abeta approaches in clinical testing, we will know in few years if the Abeta hypothesis of AD is correct.
病理学、遗传学、生物化学和药理学研究支持这样一种假说，即β-淀粉样蛋白（Abeta）肽的寡聚体在大脑中的积累可能导致阿尔茨海默病（AD）。目前用于治疗 AD 的药物仅产生有限的临床获益，并且不能治疗疾病的根本原因。在过去的 10 年中，已经发现并开发了针对 Abeta 的新治疗方法，以期改变疾病的自然病程。几种靶向 Abeta 的主动和被动免疫疗法正在临床试验中进行研究，目的是加速 AD 患者大脑中 Abeta 的清除。这些免疫方法中最先进的是 bapineuzumab，它由人源化抗 Abeta 单克隆抗体组成，目前正在两项大型后期临床试验中进行测试。干扰调节 Abeta 从淀粉样前体蛋白（APP）形成的蛋白酶的化合物也在积极研究中。不幸的是，这些蛋白酶中最具生物学吸引力的β-分泌酶（调节淀粉样蛋白形成 APP 代谢的第一步）被发现特别难以阻断，迄今为止只有一种化合物（CTS21166）进入了临床测试。相反，已经鉴定出几种调节 Abeta 产生的最后代谢步骤的γ-分泌酶抑制剂，最先进的是 LY-450139（semagacestat），目前正在进行 III 期临床开发。刺激负责 APP 非淀粉样蛋白代谢的α-分泌酶的化合物也在开发中，其中一种化合物 EHT-0202 最近开始了 II 期研究。此外，还鉴定出了可穿透大脑的 Abeta 聚集抑制剂，其中一种化合物 PBT-2 在最近完成的 II 期研究中产生了令人鼓舞的神经心理学结果。随着所有这些针对 Abeta 的方法在临床试验中，我们将在几年内知道 AD 的 Abeta 假说是否正确。
