Amyloid-β oligomers (AβOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer’s disease (AD). Considering presynaptic high energy demand and tight Ca²⁺ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AβOs was used to investigate the toxicity of AβOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AβOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AβOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca²⁺ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca²⁺ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.

淀粉样β-低聚物（AβOs）毒性导致线粒体功能障碍，导致阿尔茨海默氏病（AD）的突触衰竭。考虑到突触前的高能量需求和紧密的Ca ²⁺调节，线粒体功能受损可导致神经活动恶化和细胞死亡。在这项研究中，通过ICV（脑室内）注射AβOs诱导的AD小鼠模型用于研究AβOs对突触前功能的毒性。作为治疗方法，通过口服途径给予GUO（鸟苷）以评估对该AD模型的神经保护作用。从模型诱导开始的24小时和48小时后，分别进行了行为任务和生化分析。AβOs会损害对象识别（OR）的短期记忆并降低海马中谷氨酸的摄取和氧化。此外，AβOs减少了备用呼吸能力，降低了ATP水平，损害了Ca ²⁺处理，并导致海马突触体线粒体肿胀。鸟苷穿过血脑屏障，恢复了OR短期记忆，恢复了谷氨酸的吸收，恢复了线粒体Ca ²⁺稳态，并部分预防了线粒体肿胀。因此，这种内源性嘌呤对突触前线粒体具有神经保护作用，应考虑在AD模型中进行进一步研究。