Ionian University, Corfu, Greece.
Adv Exp Med Biol. 2020;1195:105-116. doi: 10.1007/978-3-030-32633-3_15.
Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to World Health Organization (WHO), AD is the most common cause of dementia, accounting for as many as 60-70% of senile dementia cases and affecting 47.5 million people worldwide (data from 2015) (Dementia Fact Sheet No 362. http://who.int/mediacentre/factsheets/fs362/en/ ). The median survival time after the onset of dementia ranges from 3.3 to 11.7 years (Todd et al. Int J Geriatr Psychiatry 28:1109-1124, 2013). AD is characterized as a severe, chronic, incurable, and progressive neurodegenerative disorder, associated with memory loss and cognition impairment accompanied by abnormal behavior and personality changes (Godyn et al. Pharmacol Rep 68:127-138, 2016). AD is characterized by neuronal death, which usually correlates with the appearance of key neuropathological changes, including acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of β-amyloid (Aβ plaques), intracellular neurofibrillary tangles by hyperphosphorylated tau protein deposits, neuroinflammation, and widespread neuronal loss (Godyn et al. Pharmacol Rep 68:127-138, 2016; Graham et al. Annu Rev. Med 68:413-430, 2017). The discovery of the degeneration of cholinergic neurons and the reduction of acetylcholine levels in postmortem studies of patients resulted in the use of drugs that leads to the increase of acetylcholine levels in brain (Dubois et al. Lacet Neurol 13:614-629, 2014). At present there is no preventative or curative treatment that interferes with the development of the disease. However, in recent years progress was made in the development of cholinergic drugs which have a positive effect on disease progression. Nowadays, specific drugs that can inhibit the enzyme that degrades acetylcholine are used. The development of new effective drugs involves a difficult and time-consuming process, accompanied by a very high failure rate. In the absence of effective therapies, the estimated number of people with dementia will reach 115 to 131, five million by 2050 (Dubois et al. Lacet Neurol 13:614-629, 2014; Cummings et al. Alzheimers Res Ther 6:37, 2014). Novel therapies and new targets required for developing more effective drugs for the treatment of AD patients are urgently needed.
阿尔茨海默病（AD）于 1906 年由 Alois Alzheimer 博士首次描述和诊断（Hippius 和 Neundorfer，Dialogues Clin Neurosc 5:101-108, 2003）。根据世界卫生组织（WHO）的说法，AD 是痴呆症最常见的原因，占老年痴呆症病例的 60-70%，全球有 4750 万人受到影响（2015 年数据）（第 362 号痴呆症情况说明书。http://who.int/mediacentre/factsheets/fs362/en/）。痴呆症发病后的中位生存时间为 3.3 至 11.7 年（Todd 等人，Int J Geriatr Psychiatry 28:1109-1124, 2013）。AD 是一种严重、慢性、无法治愈和进行性的神经退行性疾病，与记忆丧失和认知障碍相关，伴有异常行为和个性改变（Godyn 等人，Pharmacol Rep 68:127-138, 2016）。AD 的特征是神经元死亡，这通常与关键神经病理学变化的出现相关，包括乙酰胆碱缺乏、谷氨酸兴奋性毒性、β-淀粉样蛋白（Aβ 斑块）的细胞外沉积、由过度磷酸化的 tau 蛋白沉积物引起的细胞内神经原纤维缠结、神经炎症和广泛的神经元丢失（Godyn 等人，Pharmacol Rep 68:127-138, 2016；Graham 等人，Annu Rev. Med 68:413-430, 2017）。在对患者进行的尸检研究中发现，胆碱能神经元退化和乙酰胆碱水平降低，这导致了使用可导致大脑中乙酰胆碱水平升高的药物（Dubois 等人，Lacet Neurol 13:614-629, 2014）。目前，没有预防或治疗疾病发展的方法。然而，近年来，在开发胆碱能药物方面取得了进展，这些药物对疾病进展有积极影响。如今，使用可抑制降解乙酰胆碱的酶的特定药物。开发新的有效药物涉及一个困难和耗时的过程，并且失败率非常高。在缺乏有效疗法的情况下，预计到 2050 年，痴呆症患者的人数将达到 115 至 131 万（Dubois 等人，Lacet Neurol 13:614-629, 2014；Cummings 等人，Alzheimers Res Ther 6:37, 2014）。急需新型疗法和新靶点，以开发更有效的 AD 患者治疗药物。
