Kokkali Maria, Karali Kanelina, Thanou Evangelia, Papadopoulou Maria Anna, Zota Ioanna, Tsimpolis Alexandros, Efstathopoulos Paschalis, Calogeropoulou Theodora, Li Ka Wan, Sidiropoulou Kyriaki, Gravanis Achille, Charalampopoulos Ioannis
Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003, Greece.
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, 71003, Greece.
Mol Psychiatry. 2025 Jun;30(6):2265-2283. doi: 10.1038/s41380-024-02833-w. Epub 2024 Nov 25.
Alzheimer's Disease (AD) is an incurable and debilitating progressive, neurodegenerative disorder which is the leading cause of dementia worldwide. Neuropathologically, AD is characterized by the accumulation of Aβ amyloid plaques in the microenvironment of brain cells and neurovascular walls, chronic neuroinflammation, resulting in neuronal and synaptic loss, myelin and axonal failure, as well as significant reduction in adult hippocampal neurogenesis. The hippocampal formation is particularly vulnerable to this degenerative process, due to early dysfunction of the cholinergic circuit. Neurotrophic factors consist major regulatory molecules and their decline in AD is considered as an important cause of disease onset and progression. Novel pharmacological approaches are targeting the downstream pathways controlled by neurotrophins, such as nerve growth factor (NGF) receptors, TrkA and p75, which enhance hippocampal neurogenic capacity and neuroprotective mechanisms, and potentially counteract the neurotoxic effects of amyloid deposition. BNN27 is a non-toxic, newly developed 17-spiro-steroid analog, penetrating the blood-brain-barrier (BBB) and mimicking the neuroprotective effects of NGF, acting as selective activator of its receptors, both TrkA and p75NTR, thus promoting survival of various neuronal cell types. Our present research aims at determining whether and which aspects of the AD-related pathology, BNN27 is able to alleviate, exploring the cellular and molecular AD components and link these changes with improvements in the cognitive performance of an animal AD model, the 5xFAD mice. Our results clearly indicate that BNN27 administration significantly reduced amyloid-β load in whole brain of the animals, enhanced adult hippocampal neurogenesis, restored cholinergic function and synaptogenesis, reducing inflammatory activation and leading to significant restoration of cognitive functions. BNN27 may represent a new lead multimodal molecule with neuroprotective, neurogenic and anti-neuroinflammatory actions for developing druggable anti-Alzheimeric agents. Proteomics data are available via ProteomeXchange with the identifier PXD044699.
阿尔茨海默病（AD）是一种无法治愈且使人衰弱的进行性神经退行性疾病，是全球痴呆症的主要病因。在神经病理学上，AD的特征是β淀粉样蛋白斑块在脑细胞和神经血管壁的微环境中积累、慢性神经炎症，导致神经元和突触丧失、髓鞘和轴突功能障碍，以及成年海马神经发生显著减少。由于胆碱能回路的早期功能障碍，海马结构特别容易受到这种退行性过程的影响。神经营养因子是主要的调节分子，它们在AD中的减少被认为是疾病发生和进展的重要原因。新的药理学方法针对神经营养因子控制的下游途径，如神经生长因子（NGF）受体TrkA和p75，这些途径可增强海马神经发生能力和神经保护机制，并可能抵消淀粉样蛋白沉积的神经毒性作用。BNN27是一种新开发的无毒17-螺甾类固醇类似物，可穿透血脑屏障（BBB），模拟NGF的神经保护作用，作为其受体TrkA和p75NTR的选择性激活剂，从而促进各种神经元细胞类型的存活。我们目前的研究旨在确定BNN27是否能够缓解以及能够缓解AD相关病理学的哪些方面，探索AD的细胞和分子成分，并将这些变化与动物AD模型5xFAD小鼠认知能力的改善联系起来。我们的结果清楚地表明，给予BNN27可显著降低动物全脑中的淀粉样β蛋白负荷，增强成年海马神经发生，恢复胆碱能功能和突触形成，减少炎症激活，并导致认知功能的显著恢复。BNN27可能代表一种新的先导多模态分子，具有神经保护、神经发生和抗神经炎症作用，可用于开发可成药的抗阿尔茨海默病药物。蛋白质组学数据可通过ProteomeXchange获得，标识符为PXD044699。
