Department of Neurology, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany.
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37073, Göttingen, Germany.
J Neuroinflammation. 2024 Feb 28;21(1):62. doi: 10.1186/s12974-024-03050-6.
Presence of autoantibodies against α-synuclein (α-syn AAb) in serum of the general population has been widely reported. That such peripheral factors may be involved in central nervous system pathophysiology was demonstrated by detection of immunoglobulins (IgGs) in cerebrospinal fluid and brain of Parkinson's disease (PD) patients. Thus, blood-borne IgGs may reach the brain parenchyma through an impaired blood-brain barrier (BBB).
The present study aims to evaluate the patho-physiological impact of α-syn AAbs on primary brain cells, i.e., on spontaneously active neurons and on astrocytes. Exposure of neuron-astrocyte co-cultures to human serum containing α-syn AAbs mediated a dose-dependent reduction of spontaneous neuronal activity, and subsequent neurodegeneration. Removal specifically of α-syn AAbs from the serum prevented neurotoxicity, while purified, commercial antibodies against α-syn mimicked the neurodegenerative effect. Mechanistically, we found a strong calcium flux into neurons preceding α-syn AAbs-induced cell death, specifically through NMDA receptors. NMDA receptor antagonists prevented neurodegeneration upon treatment with α-syn (auto)antibodies. α-syn (auto)antibodies did not affect astrocyte survival. However, in presence of α-syn, astrocytes reacted to α-syn antibodies by secretion of the chemokine RANTES.
These findings provide a novel basis to explain how a combination of BBB impairment and infiltration of IgGs targeting synuclein may contribute to neurodegeneration in PD and argue for caution with α-syn immunization therapies for treatment of PD.
在普通人群的血清中存在针对α-突触核蛋白（α-syn AAb）的自身抗体已被广泛报道。这种外周因素可能参与中枢神经系统的病理生理学，这是通过在帕金森病（PD）患者的脑脊液和大脑中检测到免疫球蛋白（IgGs）来证明的。因此，血液来源的 IgG 可能通过受损的血脑屏障（BBB）到达脑实质。
本研究旨在评估 α-syn AAbs 对原代脑细胞（即自发活跃神经元和星形胶质细胞）的病理生理影响。将神经元-星形胶质细胞共培养物暴露于含有 α-syn AAbs 的人血清中，介导了自发性神经元活动的剂量依赖性减少，并随后导致神经退行性变。从血清中特异性去除 α-syn AAbs 可防止神经毒性，而纯化的、商业化的针对 α-syn 的抗体则模拟了神经退行性效应。从机制上讲，我们发现钙通量在 α-syn AAbs 诱导的细胞死亡之前强烈进入神经元，特别是通过 NMDA 受体。NMDA 受体拮抗剂可预防用 α-syn（自身）抗体治疗时的神经退行性变。α-syn（自身）抗体不影响星形胶质细胞的存活。然而，在存在 α-syn 的情况下，星形胶质细胞通过分泌趋化因子 RANTES 对 α-syn 抗体做出反应。
这些发现为解释 BBB 损伤和针对突触核蛋白的 IgG 浸润如何有助于 PD 中的神经退行性变提供了新的依据，并呼吁在使用 α-syn 免疫治疗治疗 PD 时要谨慎。
