AIMS Parkinson's disease and related disorders are devastating neurodegenerative pathologies. Since α-synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α-synuclein's detrimental effects. α-synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co-fostering Parkinson's disease. However, direct evidence linking inflammation to the harmful activities of α-synuclein oligomers or to the Parkinson's disease behavioural phenotype is lacking. METHODS To clarify whether neuroinflammation influences Parkinson's disease pathogenesis, we developed: (i) a "double-hit" approach in C57BL/6 naïve mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic "double-hit" model where lipopolysaccharides were given to A53T α-synuclein transgenic Parkinson's disease mice. RESULTS Lipopolysaccharides induced a long-lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS-activated microglia and astrocytes responded differently to the oligomers. with microglia activating further and acquiring a proinflammatory M1 phenotype, while astrocytes atrophied. In the transgenic "double-hit" A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally-induced neuroinflammation potentiates the α-synuclein oligomer's actions and aggravates cognitive deficits in A53T mice. CONCLUSIONS The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α-synucleinopathies.

中文翻译：

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周围炎症加剧帕金森病模型中 α-突触核蛋白的毒性和神经病理学


目的 帕金森病和相关疾病是破坏性的神经退行性疾病。自从 α-突触核蛋白被确定为路易体和神经突的主要成分以来，人们一直在努力阐明 α-突触核蛋白有害作用的致病机制。 α-突触核蛋白寡聚体是最有害的物种，可能招募和激活神经胶质细胞。炎症正在成为遗传易感性和共同促进帕金森病的环境因素之间的桥梁。然而，缺乏将炎症与 α-突触核蛋白寡聚物的有害活动或帕金森病行为表型联系起来的直接证据。方法 为了阐明神经炎症是否影响帕金森病的发病机制，我们开发了：（i）在 C57BL/6 幼鼠中采用“双重打击”方法，其中外周给予脂多糖，然后脑室内注射非活性寡聚物剂量； (ii)转基因“双重打击”模型，其中将脂多糖给予A53T α-突触核蛋白转基因帕金森病小鼠。结果脂多糖诱导持久的神经炎症反应，促进低聚物的有害认知活动。 LPS 激活的小胶质细胞和星形胶质细胞对寡聚物的反应不同。小胶质细胞进一步激活并获得促炎性 M1 表型，而星形胶质细胞则萎缩。在转基因“双重打击”A53T 小鼠模型中，脂多糖加剧了认知缺陷并增加了小胶质细胞增生。同样，星形胶质细胞对双重挑战的反应也不同。这些发现表明，外周诱导的神经炎症会增强 α-突触核蛋白寡聚体的作用，并加剧 A53T 小鼠的认知缺陷。 结论 外周和中枢炎症的精细管理可能提供一种有前途的治疗方法，以预防或减缓 α-突触核蛋白病的某些行为方面。