Impact of TSPO activation on Abeta-induced synaptotoxic effects - focus on learning and memory-related processes

TSPO 激活对 Abeta 诱导的突触毒性作用的影响 - 关注学习和记忆相关过程

• 批准号: 340549550
• 负责人: Professor Dr. Gerhard Rammes, Ph.D.
• 金额: --
• 依托单位: Klinik für Anästhesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/340549550?language=en
• 关键词: Impact; TSPO; activation; Abeta; induced

Memory impairment and progressive cognitive decline are the main symptoms of Alzheimer Disease (AD), a neurodegenerative disorder with increasing incidence among elderly people. The most obvious pathological feature of AD is the accumulation of beta-amyloid peptides (Abeta) in the brain, and these peptides are thought to underlie early deficits in synaptic plasticity and the resulting cognitive impairment. There is increasing clinical evidence that depression is a common antecedent of Alzheimer disease and may be an early manifestation of dementia suggesting partly overlapping biological mechanisms of these diseases. Indeed, perturbation of energy and protein homeostasis facilitating neurodegenerative processes is proposed as the unifying mechanism of depression and cerebral aging.The mitochondrial translocator protein (18 kDa) (TSPO) promotes neurosteroidogenesis in neurons and astrocytes. Interestingly, TSPO ligands have been shown to be neuroprotective and might be beneficial in the treatment of neurological and psychiatric disorders. In a recent translational study, we demonstrated that the selective and high-affinity TSPO ligand XBD173 displayed antipanic and anxiolytic efficacy in rats and humans via neurosteroidogenesis.The primary goal of this application is to elucidate the molecular mechanisms and functional consequences of TSPO activation. The fundamental question on the physiological level is: does exposure to XBD173 exert early (neuro)protective effects in the pathophysiology of AD? To address this question, we will employ methods from molecular and cell biology, monitoring the activity of neurons and animal behaviour.More specifically, XBD173 will be tested for its potential to reverse the toxic effect of Abeta on spine density, neuronal circuits and Abeta-induced synaptotoxicity against the induction of long-term potentiation (LTP), a cellular correlate for learning and memory. Finally, we will employ an animal model of AD to evaluate XBD173 for its ability to modify AD at early and late stages by reducing protein aggregates or the levels of toxic protein species and enhance cognition. TSPO knockdown/knockout models will serve to answer the question for direct and TSPO-specific mechanisms.Most previous studies have been conducted using Abeta1-40 or Abeta1-42 peptides. However, recently other Abeta species are receiving considerable attention as possible pathogens in AD due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Therefore, we will include the toxic Abeta species pyroglutamate-modified Abeta-(Abeta pE3) and nitrated Abeta (3NTyr10-Abeta).Altogether, the present proposal intends to reveal any potential beneficial mechanisms of XBD173 regarding the pathophysiology in AD such as neuronal dysfunction and reduced memory processes.

阿尔茨海默病（Alzheimer Disease，AD）是一种神经退行性疾病，在老年人中发病率越来越高，其主要症状是记忆障碍和进行性认知功能下降。AD最明显的病理特征是β-淀粉样肽（Abeta）在脑中的积累，并且这些肽被认为是突触可塑性的早期缺陷和由此产生的认知障碍的基础。越来越多的临床证据表明，抑郁症是阿尔茨海默病的常见先兆，可能是痴呆的早期表现，这表明这些疾病的生物学机制部分重叠。事实上，能量和蛋白质稳态的扰动促进神经退行性过程被认为是抑郁症和脑老化的统一机制。线粒体转运蛋白（18 kDa）（TSPO）促进神经元和星形胶质细胞中的神经类固醇生成。有趣的是，TSPO配体已被证明是神经保护性的，并可能有益于治疗神经和精神疾病。在最近的翻译研究中，我们证明了选择性和高亲和力的TSPO配体XBD 173通过神经甾体合成在大鼠和人类中显示出抗恐慌和抗焦虑的功效。生理水平上的基本问题是：暴露于XBD 173是否在AD的病理生理学中发挥早期（神经）保护作用？为了解决这个问题，我们将采用分子和细胞生物学的方法，监测神经元和动物行为的活性。更具体地说，XBD 173将被测试其逆转Abeta对脊髓密度、神经元回路和Abeta诱导的突触毒性的毒性作用的潜力，以对抗诱导长时程增强（LTP），这是一种与学习和记忆相关的细胞。最后，我们将采用AD动物模型来评估XBD 173通过减少蛋白质聚集体或毒性蛋白质种类的水平以及增强认知来在早期和晚期阶段修饰AD的能力。TSPO敲除/敲除模型将用于回答直接和TSPO特异性机制的问题。然而，最近其他Abeta物种作为AD中可能的病原体受到相当大的关注，这是由于它们在AD脑中的丰度、高聚集倾向、稳定性和细胞毒性。因此，我们将包括有毒的Abeta物种焦谷氨酸修饰的Abeta-（Abeta pE 3）和硝化的Abeta（3 NTyr 10-Abeta）。总之，本提案旨在揭示XBD 173在AD的病理生理学方面的任何潜在的有益机制，例如神经元功能障碍和记忆过程减少。