The role of endozepine diazepam binding inhibitor on the structural plasticity of dendrite spines in neurodegenerative diseases

内氮卓地西泮结合抑制剂对神经退行性疾病树突棘结构可塑性的作用

• 批准号: 511905387
• 负责人: Dr. Yuan Shi
• 金额: --
• 依托单位: Zentrum für Neuropathologie und Prionforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511905387?language=en
• 关键词: role; endozepine; diazepam; binding; inhibitor

In the central nervous system (CNS), the structural plasticity of dendritic spines, reflecting the establishment or destruction of synapses, is highly dynamic. Emerging evidence suggests that such structural alterations in synaptic connectivity, are likely the underpinning of cognitive processes in response to not only physiological stimuli but also many, if not all, neurodegenerative diseases, such as Alzheimer's disease (AD) and synucleinopathies. So far, though a few intrinsic and extrinsic modulators of the structural plasticity of dendrite spines have been identified, more are kept being discovered. Recently, we observed elevation of TSPO either upon benzodiazepine administration in WT mice or in plaque-associated microglia in the AD mouse model, leading to a global or regional decrease of dendritic spine plasticity, respectively. Such evidence prompted our interest in endogenous TSPO ligands designated by the generic term ‘endozepines’ that may regulate the dendritic spine dynamics across healthy condition and neurodegenerative diseases. One of the best-known endozepines is the diazepam binding inhibitor (DBI), a 9 kDa peptide primarily produced and released by astrocytes in the CNS, and prominently bind to TSPO with high affinity. In our preliminary work, we have observed increased dendritic spine density in WT mice upon DBI knockdown using viral vectors with shRNA driven by a U6 (cell-type unspecific) promoter, hinting DBI's role in regulating dendritic spines. On top of that, we observed a significant increase of DBI from plaque-associated astrocytes in an AD mouse model. Hence, based on these data, it is tempting to hypothesize that astrocytes and microglia intertwine in the neurodegenerative brain via the DBI-TSPO signaling pathway, which might collaboratively affect dendritic spines. In this project, we plan to (WP1) characterise the role of astrocytic DBI in regulating the structural plasticity of dendritic spines, as well as on microglial morphology and functions. After that, we will explore (WP2) whether and how the dendritic spines and microglia are to be affected in the neurodegenerative diseases upon astrocytic DBI depletion. To extend our study in a translational manner, we will then validate (WP3) our findings in post-mortem human tissues, investigating alterations of astrocytic DBI signalling and subsequent microglial synaptic engulfment in patients with neurodegenerative diseases in comparison to healthy controls. In summary, we expect these experiments will decipher the role of astrocytic DBI as a physiological modulator of dendritic spines, and may as a common therapeutic target for restoring synaptic pathology in a variety of neurodegenerative diseases.

在中枢神经系统（CNS）中，树突棘的结构可塑性是高度动态的，反映了突触的建立或破坏。新出现的证据表明，突触连通性的这种结构改变可能是认知过程的基础，不仅是对生理刺激的反应，而且对许多（如果不是全部的话）神经退行性疾病（如阿尔茨海默病（AD）和突触核蛋白病）的反应。到目前为止，虽然已经确定了一些树突棘结构塑性的内在和外在调节剂，但更多的调节剂仍在不断被发现。最近，我们在WT小鼠或AD小鼠模型中斑块相关小胶质细胞中观察到TSPO升高，分别导致整体或局部树突脊柱可塑性降低。这些证据促使我们对内源性TSPO配体的兴趣，这些配体被通用术语“endozepines”指定，可能调节健康状况和神经退行性疾病中的树突脊柱动力学。最著名的内啡肽之一是地西泮结合抑制剂（DBI），这是一种9 kDa的肽，主要由中枢神经系统的星形胶质细胞产生和释放，并以高亲和力与TSPO结合。在我们的初步工作中，我们观察到使用由U6（细胞型非特异性）启动子驱动的shRNA驱动的病毒载体敲除DBI后，WT小鼠树突棘密度增加，提示DBI在调节树突棘中的作用。最重要的是，我们在AD小鼠模型中观察到斑块相关星形胶质细胞的DBI显著增加。因此，基于这些数据，我们很容易假设星形胶质细胞和小胶质细胞在神经退行性脑中通过DBI-TSPO信号通路相互交织，这可能共同影响树突棘。在这个项目中，我们计划（WP1）表征星形细胞DBI在调节树突棘结构可塑性以及小胶质细胞形态和功能中的作用。之后，我们将探讨（WP2）在星形细胞DBI耗竭后，树突棘和小胶质细胞是否以及如何在神经退行性疾病中受到影响。为了以翻译的方式扩展我们的研究，我们将在死后的人体组织中验证（WP3）我们的发现，研究与健康对照相比，神经退行性疾病患者星形细胞DBI信号的改变和随后的小胶质突触吞噬。总之，我们期望这些实验将破译星形细胞DBI作为树突棘生理调节剂的作用，并可能作为恢复各种神经退行性疾病突触病理的共同治疗靶点。