Role of cannabinoid signalling between neurons and microglia cells in brain ageing

神经元和小胶质细胞之间的大麻素信号传导在大脑衰老中的作用

• 批准号: 265488569
• 负责人: Privatdozent Dr. Andras Bilkei-Gorzo
• 金额: --
• 依托单位: Institut für Molekulare Psychiatrie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265488569?language=en
• 关键词: Role; cannabinoid; signalling; between; neurons

We have shown previously that there is an early onset of brain ageing accompanied with increased microglial activity in the hippocampus of animals lacking CB1 receptors on GABAergic neurons. This highly unexpected result led us to the hypotheses that (1) endocannabinoid system plays a role as communication channel between GABAergic neurons and microglia and (2) cannabinoid signaling between neurons and microglia is protective against age-related changes. To test these possibilities we will evaluate in a longitudinal study the age-related cognitive and histological changes in mice lacking the main endocannabinoid synthesizing enzyme diacylglycerol lipase (DAGL) alpha and beta from microglia. Our previous results also suggested that reduced signaling between microglia and GABAergic neurons upregulates microglial activity and promotes neuroinflammation in the ageing brain. Thus, we will compare the reactivity of microglia using organotypic hippocampal culture from GABA specific CB1 knockout and microglia specific DAGL alpha and DAGL beta knockout animals. We will also compare the motility and morphology of GFP-tagged microglia transplanted to the hippocampus of wild-type and GABA/CB1-/- mice with different age. Lastly, we hypothesize that disturbed endocannabinoid signalling leads to an early onset and/or exacerbated senescence associated phenotype in microglia. To test this possibility we will compare lipofuscin accumulation, dynamics of epigenetic and gene expression changes and the phenotype of the microglia cells isolated from the brain of wild-type and GABA/CB1-/- animals with different age.

我们以前已经表明，在GABA能神经元上缺乏CB 1受体的动物的海马中，伴随着小胶质细胞活性的增加，存在脑老化的早期发作。这一非常出乎意料的结果使我们提出了以下假设：（1）内源性大麻素系统作为GABA能神经元和小胶质细胞之间的通讯通道发挥作用，以及（2）神经元和小胶质细胞之间的大麻素信号传导对年龄相关变化具有保护作用。为了测试这些可能性，我们将在一项纵向研究中评估缺乏来自小胶质细胞的主要内源性大麻素合成酶二酰甘油脂肪酶（DAGL）α和β的小鼠中与年龄相关的认知和组织学变化。我们之前的研究结果也表明，小胶质细胞和GABA能神经元之间的信号传导减少会上调小胶质细胞的活性，并促进衰老大脑中的神经炎症。因此，我们将使用来自GABA特异性CB 1敲除和小胶质细胞特异性DAGL α和DAGL β敲除动物的器官型海马培养物比较小胶质细胞的反应性。我们还将比较移植到不同年龄的野生型和GABA/CB 1-/-小鼠海马中的GFP标记的小胶质细胞的运动性和形态学。最后，我们假设，干扰内源性大麻素信号传导导致小胶质细胞中的早发性和/或加剧衰老相关表型。为了测试这种可能性，我们将比较脂褐素积累，表观遗传和基因表达变化的动力学和从不同年龄的野生型和GABA/CB 1-/-动物的脑中分离的小胶质细胞的表型。