INSERM UMR_S 1072, Aix-Marseille Université, Marseille, France.
Protein Sci. 2020 Aug;29(8):1748-1759. doi: 10.1002/pro.3906. Epub 2020 Jul 13.
After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β-amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca permeable pores in the membranes of brain cells. By triggering an intracellular Ca overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This "histidine trick" can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti-oligomer targets will provide innovative opportunities to find an efficient cure. A "full efficient" solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.
经过三十年的虚假希望和失败，现在有了一条针对阿尔茨海默病（AD）实际根本原因的治疗药物管道。这些化合物挑战了以前专注于淀粉样蛋白斑块中β-淀粉样肽（Aβ）聚集的旧范式，旨在防止在脑细胞的膜中形成 Ca 渗透性孔的 Aβ 低聚物的神经毒性。通过触发细胞内 Ca 过载，Aβ 低聚物诱导包括氧化应激、tau 过度磷酸化和神经元丧失在内的一连串神经毒性事件。针对任何 Ca 进入后的步骤（例如 tau）都不会解决疾病的根本原因。因此，防止 Aβ 低聚物的形成和/或阻断其毒性实质上是阻止 AD 进展的最佳方法。已有三种抗低聚物化合物类别：抗体、合成肽和小分子药物。基于计算机的肽（AmyP53）和单克隆抗体（PMN310）的独立设计汇聚到一个关键的寡聚体中和位点：组氨酸基序（H13/H14）。这种“组氨酸技巧”可以被视为 Aβ 在对抗 AD 中的阿喀琉斯之踵。此外，脂筏，尤其是神经节苷脂，在 Aβ 低聚物的形成和毒性中发挥着关键作用。将 AD 视为一种膜紊乱，将神经节苷脂视为关键的抗低聚物靶标，将为寻找有效的治疗方法提供创新机会。作为一种“完全有效的”解决方案，还需要负担得起任何人的费用，因为患者人数呈指数级增长，影响到全球各地。
