Department of Pharmacology and Department of Toxicology and Narcotics, National Research Centre, Cairo, Egypt.
CNS Neurol Disord Drug Targets. 2011 Jun;10(4):459-85. doi: 10.2174/187152711795563976.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which impairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the neurodegenerative process. Extracellular as well as intracellular deposition of beta-amyloid or Abeta (Abeta) protein, intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages. In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult neurogenesis may contribute to the pathogenesis of AD and other neurodegenerative disorders. An attempt at mobilizing this endogenous pool of resident stem-like cells provides another attractive approach for the treatment of AD. Studies in patients with AD indicated decreased hippocampal volume derived by neurodegeneration. Intriguingly, many drugs including antidepressants, lithium, acetyl cholinesterase inhibitors, and ginkgo biloba, were able to enhance the impaired neurogenesis in this disease process. This paved the way towards exploring the possible pharmacological manipulation of neurogenesis which would offer an alternative approach for the treatment of AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，会损害受影响个体的记忆和智力能力。情节记忆和语义记忆的丧失是早期和主要特征。基底前脑胆碱能系统是受神经退行性过程影响最大的神经元群体。β-淀粉样蛋白或 Abeta（Abeta）蛋白的细胞外和细胞内沉积、神经纤维缠结的细胞内形成和神经元丢失是 AD 的神经病理学标志。在过去的几年中，人们希望细胞替代疗法能够通过补偿丢失的神经元系统来提供治疗。从胚胎和成人组织中获得的干细胞，并移植到小鼠或大鼠的完整大脑中，大多数情况下会被整合到宿主实质中，并分化为功能性神经谱系。在受损的大脑中，干细胞表现出向大脑受损区域的靶向迁移，在那里它们定植、增殖并成熟为功能性神经元。神经前体细胞可以静脉内给予，并且仍然迁移到脑损伤区域，诱导功能恢复。AD 动物模型的观察结果提供了证据，表明移植的干细胞或神经前体细胞（NPC）存活、迁移并分化为胆碱能神经元、星形胶质细胞和少突胶质细胞，改善了学习/记忆缺陷。除了替代丢失或受损的细胞外，干细胞还刺激内源性神经前体细胞、增强结构神经可塑性、下调促炎细胞因子和神经元凋亡死亡。干细胞还可以被基因修饰以将生长因子表达到大脑中。在过去的几年中，有证据表明哺乳动物的成年大脑保留了从神经干细胞/祖细胞产生新神经元的能力。低效的成年神经发生可能有助于 AD 和其他神经退行性疾病的发病机制。动员这种内源性驻留干细胞样细胞池提供了另一种有吸引力的 AD 治疗方法。AD 患者的研究表明，神经退行性变导致海马体积减小。有趣的是，许多药物，包括抗抑郁药、锂、乙酰胆碱酯酶抑制剂和银杏叶，能够增强这种疾病过程中受损的神经发生。这为探索神经发生的可能药理学操纵铺平了道路，这将为 AD 的治疗提供一种替代方法。
