Kakoty Violina, C Sarathlal K, Yang Chih-Hao, Kumari Shobha, Dubey Sunil Kumar, Taliyan Rajeev
Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India, 333031.
Department of Pharmacology, Taipei Medical University, Taipei, Taiwan, 110.
Mol Neurobiol. 2022 May;59(5):2659-2677. doi: 10.1007/s12035-022-02741-6. Epub 2022 Feb 10.
Alzheimer type of dementia is accompanied with progressive loss of cognitive function that directly correlates with accumulation of amyloid beta plaques. It is known that Fibroblast growth factor 21 (FGF21), a metabolic hormone, with strong neuroprotective potential, is induced during oxidative stress in Alzheimer's disease. Interestingly, FGF21 cross-talks with autophagy, a mechanism involved in the clearance of abnormal protein aggregate. Moreover, autophagy activation by Rapamycin delivers neuroprotective role in Alzheimer's disease. However, the synergistic neuroprotective efficacy of overexpressed FGF21 along with Rapamycin is not yet investigated. Therefore, the present study examined whether overexpressed FGF21 along with autophagy activation ameliorated neurodegenerative pathology in Alzheimer's disease. We found that cognitive deficits in rats with intracerebroventricular injection of Amyloid beta oligomers were restored when injected with FGF21-expressing lentiviral vector combined with Rapamycin. Furthermore, overexpression of FGF21 along with Rapamycin downregulated protein levels of Amyloid beta and phosphorylated tau and expression of major autophagy proteins along with stabilization of oxidative stress. Moreover, FGF21 overexpressed rats treated with Rapamycin revamped the neuronal density as confirmed by histochemical, cresyl violet and immunofluorescence analysis. These results generate compelling evidence that Alzheimer's disease pathology exacerbated by oligomeric amyloid beta may be restored by FGF21 supplementation combined with Rapamycin and thus present an appropriate treatment paradigm for people affected with Alzheimer's disease.
阿尔茨海默病型痴呆症伴随着认知功能的逐渐丧失，这与β淀粉样蛋白斑块的积累直接相关。已知成纤维细胞生长因子21（FGF21）作为一种代谢激素，具有强大的神经保护潜力，在阿尔茨海默病的氧化应激过程中被诱导产生。有趣的是，FGF21与自噬相互作用，自噬是一种参与清除异常蛋白质聚集体的机制。此外，雷帕霉素激活自噬在阿尔茨海默病中发挥神经保护作用。然而，过表达的FGF21与雷帕霉素协同的神经保护功效尚未得到研究。因此，本研究检测了过表达的FGF21与自噬激活是否能改善阿尔茨海默病的神经退行性病变。我们发现，当向脑室内注射β淀粉样寡聚体的大鼠注射表达FGF21的慢病毒载体并联合雷帕霉素时，其认知缺陷得到了恢复。此外，FGF21与雷帕霉素的过表达下调了β淀粉样蛋白和磷酸化tau蛋白的水平，以及主要自噬蛋白的表达，并稳定了氧化应激。此外，经组织化学、甲酚紫和免疫荧光分析证实，用雷帕霉素处理过表达FGF21的大鼠可恢复神经元密度。这些结果提供了令人信服的证据，即由寡聚β淀粉样蛋白加剧的阿尔茨海默病病理可能通过补充FGF21并联合雷帕霉素得到恢复，从而为阿尔茨海默病患者提供了一种合适的治疗模式。
