Sakiyama Hiroshi, Baba Kousuke, Kimura Yasuyoshi, Ogawa Kotaro, Nishiike Ujiakira, Hayakawa Hideki, Yoshida Miki, Aguirre Cesar, Ikenaka Kensuke, Nagano Seiichi, Mochizuki Hideki
Department of Neurology, Osaka University, Graduate School of Medicine, Osaka, Japan.
Department of Neurology, Osaka University, Graduate School of Medicine, Osaka, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Neurochem Int. 2025 Jan;182:105906. doi: 10.1016/j.neuint.2024.105906. Epub 2024 Nov 23.
Parkinson's disease (PD) is characterized by the formation of α-synuclein (α-syn) aggregates, which lead to dopaminergic neuronal degeneration. The incidence of PD increases with age, and senescence is considered to be a major risk factor for PD. In this study, we evaluated the effect of senescence on PD pathology using α-synuclein preformed fibrils (PFF) injection model in senescence-accelerated mice. We injected PFF into the substantia nigra (SN) of senescence-accelerated prone 8 (SAMP8) mice and senescence-accelerated resistant 1 (SAMR1) mice. At 24 weeks after injection of saline or PFF, we found that SAMP8 mice injected with PFF exhibited robust Lewy pathology and exacerbated degeneration of dopaminergic neurons in the SN compared to PFF-injected SAMR1 mice. We further observed an increase in the number of Iba1-positive cells in the brains of PFF-injected SAMP8 mice. RNA sequencing revealed that several genes related to neuroinflammation were upregulated in the brains of PFF-injected SAMP8 mice compared to SAMR1 mice. Inflammatory chemokine CC-chemokine ligand 21 (CCL21) was upregulated in PFF-injected SAMP8 mice and expressed in the glial cells of these mice. Our research indicates that accelerated senescence leads to persistent neuroinflammation, which plays an important role in the exacerbation of α-synucleinopathy.
帕金森病（PD）的特征是α-突触核蛋白（α-syn）聚集体的形成，这会导致多巴胺能神经元变性。PD的发病率随年龄增长而增加，衰老被认为是PD的主要危险因素。在本研究中，我们使用α-突触核蛋白预形成纤维（PFF）注射模型，在加速衰老小鼠中评估了衰老对PD病理的影响。我们将PFF注射到加速衰老易感8（SAMP8）小鼠和加速衰老抗性1（SAMR1）小鼠的黑质（SN）中。在注射生理盐水或PFF后24周，我们发现与注射PFF的SAMR1小鼠相比，注射PFF的SAMP8小鼠表现出强烈的路易小体病理变化，且SN中多巴胺能神经元的变性加剧。我们进一步观察到，注射PFF的SAMP8小鼠大脑中Iba1阳性细胞数量增加。RNA测序显示，与注射PFF的SAMR1小鼠相比，注射PFF的SAMP8小鼠大脑中几个与神经炎症相关的基因上调。炎症趋化因子CC趋化因子配体21（CCL21）在注射PFF的SAMP8小鼠中上调，并在这些小鼠的神经胶质细胞中表达。我们的研究表明，加速衰老会导致持续性神经炎症，这在α-突触核蛋白病的加重中起重要作用。
