Abstract：
BACKGROUND: The accumulation of beta-amyloid peptide (Aβ) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer\'s disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aβ toxicity. Recent research has demonstrated that intrahippocampal Aβ can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer\'s disease.
OBJECTIVE: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus.
METHODS: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice.
RESULTS: The mice that received Aβ1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups.
CONCLUSIONS: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.
OBJECTIVE: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus.
METHODS: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice.
RESULTS: The mice that received Aβ1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups.
CONCLUSIONS: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.
摘要：
背景：前脑中β-淀粉样肽（Aβ）的积累导致阿尔茨海默病的认知功能障碍和神经变性。研究表明，具有一致的认知活跃生活方式的个体不太容易受到Aβ毒性的影响。最近的研究表明，海马内Aβ可以影响儿茶酚胺能释放和空间记忆。有趣的是,已发现暴露于新奇刺激刺激海马中儿茶酚胺的释放。然而,反复增强儿茶酚胺活性是否能有效缓解阿尔茨海默病患者的认知障碍仍不确定。
目的：我们的主要目的是调查反复暴露于新颖性是否可以使认知弹性对Aβ。这种保护可以通过调节海马体内的儿茶酚胺能活性来实现。
方法：为了研究这一假设，我们对小鼠进行三种不同的条件-标准住房（SH），重复新奇(11月)，或一个月的日常社交互动（Soc）。然后，我们在海马内输注盐溶液（SS）或Aβ（Aβ1-42）寡聚物，并在莫里斯水迷宫（MWM）中测量空间记忆恢复。在独立的小鼠组中评估使用体内微透析的体视学分析和细胞外基线多巴胺水平。
结果：接受Aβ1-42海马内输注并保持在SH或Soc条件下的小鼠表现出受损的空间记忆恢复。相比之下,接受11月方案的动物表现出显著的韧性，即使在海马内输注Aβ1-42后，也显示出强的空间记忆表达。立体分析表明，与Nov组相比，Aβ1-42输注减少了SH或Soc小鼠的酪氨酸羟化酶轴突长度。因此，Nov组海马细胞外多巴胺水平显著升高。
结论：这些令人信服的结果证明了重复的新奇暴露可能会增强多巴胺能系统并减轻Aβ1-42的毒性作用。他们还强调了治疗和预防AD的新的和有前途的治疗途径。尤其是在早期阶段。
目的：我们的主要目的是调查反复暴露于新颖性是否可以使认知弹性对Aβ。这种保护可以通过调节海马体内的儿茶酚胺能活性来实现。
方法：为了研究这一假设，我们对小鼠进行三种不同的条件-标准住房（SH），重复新奇(11月)，或一个月的日常社交互动（Soc）。然后，我们在海马内输注盐溶液（SS）或Aβ（Aβ1-42）寡聚物，并在莫里斯水迷宫（MWM）中测量空间记忆恢复。在独立的小鼠组中评估使用体内微透析的体视学分析和细胞外基线多巴胺水平。
结果：接受Aβ1-42海马内输注并保持在SH或Soc条件下的小鼠表现出受损的空间记忆恢复。相比之下,接受11月方案的动物表现出显著的韧性，即使在海马内输注Aβ1-42后，也显示出强的空间记忆表达。立体分析表明，与Nov组相比，Aβ1-42输注减少了SH或Soc小鼠的酪氨酸羟化酶轴突长度。因此，Nov组海马细胞外多巴胺水平显著升高。
结论：这些令人信服的结果证明了重复的新奇暴露可能会增强多巴胺能系统并减轻Aβ1-42的毒性作用。他们还强调了治疗和预防AD的新的和有前途的治疗途径。尤其是在早期阶段。
