Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Department of Biotechnology and Life Sciences, Università degli Studi dell'Insubria, Varese Italy, and The Protein Factory Research Center, Università degli studi dell'Insubria and Politecnico di Milano, Milano, Italy.
Brain Behav Immun. 2018 Mar;69:591-602. doi: 10.1016/j.bbi.2018.02.012. Epub 2018 Feb 16.
Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice. In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.
α-突触核蛋白寡聚体（α-synOs）是神经核蛋白病发病机制中的关键因素。尽管神经炎症与α-syn 的关系仍不清楚，但越来越多的证据表明，细胞外部分激活神经胶质细胞，导致神经元损伤。本研究使用急性小鼠模型，探讨了 α-synOs 是否会在神经炎症的情况下引起记忆障碍，并研究 Toll 样受体 2 和 4（TLR2 和 TLR4）的参与情况。结果发现，α-synOs 与海马神经胶质激活相关，导致小鼠记忆形成障碍。在脑切片上，α-synOs 抑制长时程增强。吲哚美辛和布洛芬可预防 α-synOs 介导的有害作用。此外，虽然 TLR2 功能抑制剂抗体可预防记忆缺陷，但寡聚体在 TLR4 基因敲除小鼠中引起记忆缺陷。综上所述，仅 α-synOs 就可引起记忆障碍，可能抑制突触可塑性。α-synOs 导致海马神经胶质增生，与记忆障碍有关。此外，虽然寡聚体介导的有害作用依赖于 TLR2，但排除了 TLR4 的参与。
