Zota Ioanna, Chanoumidou Konstantina, Gravanis Achille, Charalampopoulos Ioannis
Department of Pharmacology, Medical School, University of Crete, Heraklion, Greece.
Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
Front Cell Neurosci. 2024 Sep 2;18:1422130. doi: 10.3389/fncel.2024.1422130. eCollection 2024.
Alzheimer's Disease (AD) is a chronic neurodegenerative disorder constituting the most common form of dementia (60%-70% of cases). Although AD presents majorly a neurodegenerative pathology, recent clinical evidence highlights myelin impairment as a key factor in disease pathogenesis. The lack of preventive or restorative treatment is emphasizing the need to develop novel therapeutic approaches targeting to the causes of the disease. Recent studies in animals and patients have highlighted the loss of myelination of the neuronal axons as an extremely aggravating factor in AD, in addition to the formation of amyloid plaques and neurofibrillary tangles that are to date the main pathological hallmarks of the disease. Myelin breakdown represents an early stage event in AD. However, it is still unclear whether myelin loss is attributed only to exogenous factors like inflammatory processes of the tissue or to impaired oligodendrogenesis as well. Neurotrophic factors are well established protective molecules under many pathological conditions of the neural tissue, contributing also to proper myelination. Due to their inability to be used as drugs, many research efforts are focused on substituting neurotrophic activity with small molecules. Our research team has recently developed novel micromolecular synthetic neurotrophin mimetics (MNTs), selectively acting on neurotrophin receptors, and thus offering a unique opportunity for innovative therapies against neurodegenerative diseases. These small sized, lipophilic molecules address the underlying biological effect of these diseases (neuroprotective action), but also they exert significant neurogenic actions inducing neuronal replacement of the disease areas. One of the significant neurotrophin molecules in the Central Nervous System is Brain-Derived-Neurotrophin-Factor (BDNF). BDNF is a neurotrophin that not only supports neuroprotection and adult neurogenesis, but also mediates pro-myelinating effects in the CNS. BDNF binds with high-affinity on the TrkB neurotrophin receptor and enhances myelination by increasing the density of oligodendrocyte progenitor cells (OPCs) and playing an important role in CNS myelination. Conclusively, in the present review, we discuss the myelin pathophysiology in Alzheimer's Diseases, as well as the role of neurotrophins, and specifically BDNF, in myelin maintenance and restoration, revealing its valuable therapeutic potential against AD.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，是痴呆最常见的形式（占病例的60%-70%）。尽管AD主要表现为神经退行性病变，但最近的临床证据强调髓鞘损伤是疾病发病机制的关键因素。缺乏预防性或恢复性治疗凸显了开发针对疾病病因的新型治疗方法的必要性。最近在动物和患者中的研究强调，除了淀粉样斑块和神经原纤维缠结（迄今为止该疾病的主要病理特征）的形成外，神经元轴突髓鞘形成的丧失是AD中一个极其加重的因素。髓鞘破坏是AD的早期事件。然而，髓鞘丢失是否仅归因于外源性因素，如组织的炎症过程，还是也归因于少突胶质细胞生成受损，仍不清楚。神经营养因子在神经组织的许多病理状况下是公认的保护性分子，也有助于正常的髓鞘形成。由于它们不能用作药物，许多研究工作集中于用小分子替代神经营养活性。我们的研究团队最近开发了新型小分子合成神经营养因子模拟物（MNTs），其选择性作用于神经营养因子受体，从而为针对神经退行性疾病的创新疗法提供了独特机会。这些小尺寸的亲脂性分子解决了这些疾病的潜在生物学效应（神经保护作用），而且它们还发挥显著的神经生成作用，诱导疾病区域的神经元替代。中枢神经系统中重要的神经营养因子分子之一是脑源性神经营养因子（BDNF）。BDNF是一种神经营养因子，不仅支持神经保护和成年神经发生，还介导中枢神经系统中的促髓鞘形成作用。BDNF以高亲和力与TrkB神经营养因子受体结合，并通过增加少突胶质前体细胞（OPCs）的密度来增强髓鞘形成，在中枢神经系统髓鞘形成中起重要作用。总之，在本综述中，我们讨论了阿尔茨海默病中的髓鞘病理生理学，以及神经营养因子，特别是BDNF，在髓鞘维持和恢复中的作用，揭示了其针对AD的宝贵治疗潜力。
