Cimen Yasin Ali, Elibol Birsen, Korkmaz Nur Damla, Yuzgulec Mazlum, Kinsiz Beyza, Kutlu Selim, Ustunova Savas
Department of Physiology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey.
Department of Physiology, Faculty of Medicine, Yalova University, Yalova, Turkey.
J Neurosci Res. 2025 Aug;103(8):e70070. doi: 10.1002/jnr.70070.
Melatonin and its receptors play a primary role in regulating circadian rhythms, which are frequently disrupted in patients with Alzheimer's disease (AD). Furthermore, there is increasing evidence that the use of a ketogenic diet (KD) delays the onset of AD. Therefore, we aimed to investigate whether KD has an ameliorative effect on AD through the regulation of melatonin receptors. In this study, male Sprague-Dawley rats were divided into three groups: sham, AD, and KD. At the end of KD supplementation, behavioral parameters were determined by the Morris Water Maze. Melatonin levels, protein expression levels, and immunoreactivity of MT1-MT2 in thehippocampus and striatum were determined by ELISA, Western blotting, and immunofluorescence staining, respectively. As a result, KD improved memory decline in AD rats. Also, KD increased melatonin levels in the hippocampus but did not affect striatum melatonin levels. MT1 expression tended to increase in the hippocampus of the AD group, while MT2 expression decreased. On the contrary, KD treatment increased both MT1 and MT2 expressions. In the striatum, there was no change in MT1 expression in the AD and KD groups, but MT2 expression increased in the AD group compared with the sham group and was suppressed in the KD group. In addition, KD treatment reduced streptozotocin-induced apoptosis and neuroinflammation in the hippocampus and striatum. Our results suggest that KD may improve AD-associated inflammation and apoptosis by altering melatonin levels and the expression of MT2 receptors in the hippocampus and striatum. Therefore, KD may be a promising preventive and therapeutic option for AD.
褪黑素及其受体在调节昼夜节律中起主要作用，而昼夜节律在阿尔茨海默病（AD）患者中经常被打乱。此外，越来越多的证据表明，生酮饮食（KD）可延缓AD的发病。因此，我们旨在研究KD是否通过调节褪黑素受体对AD具有改善作用。在本研究中，雄性Sprague-Dawley大鼠被分为三组：假手术组、AD组和KD组。在补充KD结束时，通过莫里斯水迷宫测定行为参数。分别通过ELISA、蛋白质印迹法和免疫荧光染色法测定海马体和纹状体中褪黑素水平、蛋白质表达水平以及MT1-MT2的免疫反应性。结果显示，KD改善了AD大鼠的记忆衰退。此外，KD增加了海马体中的褪黑素水平，但不影响纹状体中的褪黑素水平。AD组海马体中MT1表达有增加趋势，而MT2表达下降。相反，KD处理增加了MT1和MT2的表达。在纹状体中，AD组和KD组的MT1表达没有变化，但与假手术组相比，AD组的MT2表达增加，而KD组的MT2表达受到抑制。此外，KD处理减少了链脲佐菌素诱导的海马体和纹状体中的细胞凋亡和神经炎症。我们的结果表明，KD可能通过改变海马体和纹状体中的褪黑素水平以及MT2受体的表达来改善与AD相关的炎症和细胞凋亡。因此，KD可能是一种有前景的AD预防和治疗选择。
