Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder characterized by irreversible cognitive deficits and memory dysfunction. Dopamine is the most abundant catecholaminergic neurotransmitter in the brain which regulates motivation, reward, movement, and cognition. Recently, increasing evidences have shown that dopaminergic system is disturbed in AD conditions, and pharmacological interventions targeting dopamine D1 receptor (DRD1) exhibit certain therapeutic benefits in AD models. However, the underlying link between DRD1 and AD remains elusive. This study sought to test whether the selective DRD1 agonist A-68930 could improve streptozotocin (STZ)-induced cognitive impairment in mice. Here we found that A-68930 treatment through intraperitoneal injection efficiently alleviated STZ-induced cognitive deficits in mice. Moreover, our mechanism researches revealed that the DRD1 signaling induced by A-68930 significantly rescued STZ-induced mitochondrial biogenesis deficit, mitochondrial dysfunction, Aβ overexpression, and tau phosphorylation in mice hippocampus and cortex and SH-SY5Y cells, which may be mediated through stimulating AMPK/PGC-1α pathway. This study indicates that DRD1 agonist A-68930 can improve STZ-induced cognitive deficits and mitochondrial dysfunction in vivo and in vitro, and DRD1 may represent an appropriate target candidate for AD drug development.

阿尔茨海默病 (AD) 是最普遍的神经退行性疾病，其特征是不可逆的认知缺陷和记忆功能障碍。多巴胺是大脑中最丰富的儿茶酚胺能神经递质，可调节动机、奖赏、运动和认知。最近，越来越多的证据表明多巴胺能系统在 AD 条件下受到干扰，针对多巴胺 D1 受体 (DRD1) 的药物干预在 AD 模型中表现出一定的治疗益处。然而，DRD1 和 AD 之间的潜在联系仍然难以捉摸。本研究旨在测试选择性 DRD1 激动剂 A-68930 是否可以改善链脲佐菌素 (STZ) 诱导的小鼠认知障碍。在这里，我们发现通过腹腔注射的 A-68930 治疗有效地缓解了 STZ 诱导的小鼠认知缺陷。而且，我们的机制研究表明，A-68930 诱导的 DRD1 信号通路显着挽救了 STZ 诱导的小鼠海马和皮质以及 SH-SY5Y 细胞的线粒体生物合成缺陷、线粒体功能障碍、Aβ 过表达和 tau 磷酸化，这可能是通过刺激 AMPK/ PGC-1α途径。本研究表明，DRD1 激动剂 A-68930 可在体内和体外改善 STZ 诱导的认知缺陷和线粒体功能障碍，DRD1 可能代表 AD 药物开发的合适靶标候选物。这可能是通过刺激 AMPK/PGC-1α 通路介导的。本研究表明，DRD1 激动剂 A-68930 可在体内和体外改善 STZ 诱导的认知缺陷和线粒体功能障碍，DRD1 可能代表 AD 药物开发的合适靶标候选物。这可能是通过刺激 AMPK/PGC-1α 通路介导的。该研究表明，DRD1 激动剂 A-68930 在体内和体外可以改善 STZ 诱导的认知缺陷和线粒体功能障碍，并且 DRD1 可能代表 AD 药物开发的合适靶标候选物。