Sharma Monika, Sharma Nishant, Khairnar Amit
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Palaj, Ahmedabad, Gandhinagar, 382355, Gujarat, India.
International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic, ICRC, FNUSA, Brno, Czech Republic.
Neurochem Res. 2023 May;48(5):1543-1560. doi: 10.1007/s11064-022-03847-y. Epub 2022 Dec 26.
Accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Previous studies suggest that α-syn pathology may originate from the olfactory bulb (OB) or gut in response to an unknown pathogen and later progress to the different brain regions. Aging is viewed as the utmost threat to PD development. Therefore, studies depicting the role of age in α-syn accumulation and its progression in PD are important. In the present study, we gave intranasal rotenone microemulsion for 6 weeks in 12-month-old female BALB/c mice and found olfactory dysfunction after 4 and 6 weeks of rotenone administration. Interestingly, motor impairment was observed only after 6 weeks. The animals were sacrificed after 6 weeks to perform western blotting and immunohistochemical studies to detect α-syn pathology, neuroinflammation and neurodegeneration. We found α-syn accumulation in OB, striatum, substantia nigra (SN) and cortex. Importantly, we found significant glial cell activation and neurodegeneration in all the analysed regions which were absent in our previous published studies with 3 months old mice even after they were exposed to rotenone for 9 weeks indicating age is a crucial factor for α-syn induced neuroinflammation and neurodegeneration. We also observed increased iron accumulation in SN of rotenone-exposed aged mice. Moreover, inflammaging was observed in OB and striatum of 12-month-old BALB/c mice as compared to 3-month-old BALB/c mice. In conclusion, there is a difference in sensitivity between adult and aged mice in the development and progression of α-syn pathology and subsequent neurodegeneration, for which inflammaging might be the crucial probable mechanism.
α-突触核蛋白（α-syn）的积累是帕金森病（PD）发病机制的核心。先前的研究表明，α-syn病理学可能起源于嗅球（OB）或肠道，以应对未知病原体，随后进展到不同的脑区。衰老被视为PD发展的最大威胁。因此，描述年龄在α-syn积累及其在PD中的进展中的作用的研究很重要。在本研究中，我们对12月龄雌性BALB/c小鼠鼻内给予鱼藤酮微乳剂6周，发现在给予鱼藤酮4周和6周后出现嗅觉功能障碍。有趣的是，仅在6周后观察到运动障碍。6周后处死动物，进行蛋白质免疫印迹和免疫组织化学研究，以检测α-syn病理学、神经炎症和神经退行性变。我们发现α-syn在OB、纹状体、黑质（SN）和皮质中积累。重要的是，我们发现在所有分析区域中都有显著的胶质细胞活化和神经退行性变，而在我们之前发表的对3月龄小鼠的研究中，即使它们暴露于鱼藤酮9周后也没有出现这些情况，这表明年龄是α-syn诱导神经炎症和神经退行性变的关键因素。我们还观察到鱼藤酮暴露的老年小鼠SN中铁积累增加。此外，与3月龄BALB/c小鼠相比，在12月龄BALB/c小鼠的OB和纹状体中观察到炎症衰老。总之，成年小鼠和老年小鼠在α-syn病理学的发展和进展以及随后的神经退行性变方面存在敏感性差异，炎症衰老可能是关键的潜在机制。
