Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai 200233, China.
School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Cell Rep Med. 2024 May 21;5(5):101543. doi: 10.1016/j.xcrm.2024.101543. Epub 2024 May 1.
Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.
老年人认知障碍与胆汁酸（BA）代谢改变有关。本研究观察到老年人群、轻度认知障碍、阿尔茨海默病和衰老啮齿动物血清结合型初级胆汁酸（CPBA）和氨水平升高，女性变化更为明显。这些变化与回肠顶端钠-胆汁酸转运体（ASBT）表达增加、海马突触丢失以及啮齿动物大脑 CPBA 和氨水平升高相关。体外实验证实 CPBA、牛磺胆酸和氨诱导突触丢失。使用 ASBT 激活剂或抑制剂来操纵肠道 BA 转运，可证明其对大脑 CPBA 和氨水平以及啮齿动物认知下降的影响。此外，给予肠道 BA 螯合剂考来烯胺可缓解认知障碍，使衰老小鼠的 CPBA 和氨恢复正常。这些发现强调了靶向肠道 BA 吸收作为治疗与年龄相关认知障碍的策略的潜力。
