Rosenstein Igal, Novakova Lenka, Kvartsberg Hlin, Nordin Anna, Rasch Sofia, Rembeza Elzbieta, Sandgren Sofia, Malmeström Clas, Fruhwürth Stefanie, Axelsson Markus, Blennow Kaj, Zetterberg Henrik, Lycke Jan
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Blå Stråket 7, 413 45, Gothenburg, Sweden.
Region Västra Götaland, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
J Neuroinflammation. 2024 Dec 13;21(1):320. doi: 10.1186/s12974-024-03315-0.
The Gas6/TAM (Tyro3, Axl, and Mer) receptor system has been implicated in demyelination and delayed remyelination in experimental animal models, but data in humans are scarce. We aimed to investigate the role of Gas6/TAM in neurodegenerative processes in multiple sclerosis (MS).
From a prospective 5-year follow-up study, soluble Gas6/TAM biomarkers were analyzed in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) at baseline in patients with relapsing-remitting MS (RRMS) (n = 40), progressive MS (PMS) (n = 20), and healthy controls (HC) (n = 25). Brain volumes, including myelin content (MyC) and white matter (WM) were measured by synthetic magnetic resonance imaging at baseline, 12 months, and 60-month follow-up. Associations with brain volume changes were investigated in multivariable linear regression models. Gas6/TAM concentrations were also determined at 12 months follow-up in RRMS to assess treatment response.
Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS vs. RRMS and HC. Mer was higher in PMS vs. HC. Tyro3 and Gas6 were associated with reduced WM (β = 25.5, 95% confidence interval [CI] [6.11-44.96, p = 0.012; β = 11.4, 95% CI [0.42-22.4], p = 0.042, respectively) and MyC (β = 7.95, 95%CI [1.84-14.07], p = 0.012; β = 4.4, 95%CI [1.04-7.75], p = 0.012 respectively) at 60 months. Patients with evidence of remyelination at last follow-up had lower baseline soluble Tyro3 (p = 0.033) and Gas6 (p = 0.014). Except Mer, Gas6/TAM concentrations did not change with treatment in RRMS.
Our data indicate a potential role for the Gas6/TAM receptor system in neurodegenerative processes influencing demyelination and ineffective remyelination.
Gas6/TAM（Tyro3、Axl和Mer）受体系统在实验动物模型的脱髓鞘和延迟髓鞘再生中发挥作用，但人类相关数据较少。我们旨在研究Gas6/TAM在多发性硬化症（MS）神经退行性变过程中的作用。
在一项为期5年的前瞻性随访研究中，采用酶联免疫吸附测定（ELISA）法，对复发缓解型MS（RRMS）患者（n = 40）、进展型MS（PMS）患者（n = 20）和健康对照者（HC）（n = 25）的脑脊液（CSF）中的可溶性Gas6/TAM生物标志物进行基线分析。在基线、12个月和60个月随访时，通过合成磁共振成像测量脑容量，包括髓鞘含量（MyC）和白质（WM）。在多变量线性回归模型中研究与脑容量变化的相关性。还在RRMS患者12个月随访时测定Gas6/TAM浓度，以评估治疗反应。
与RRMS和HC相比，PMS患者中Tyro3、Axl和Gas6的基线浓度显著更高。与HC相比，PMS患者中Mer更高。在60个月时，Tyro3和Gas6与WM减少相关（β分别为25.5，95%置信区间[CI][6.11 - 44.96]，p = 0.012；β为11.4，95%CI[0.42 - 22.4]，p = 0.042），与MyC减少相关（β分别为7.95，95%CI[1.84 - 14.07]，p = 0.012；β为4.4，95%CI[1.04 - 7.75]，p = 0.012）。在最后一次随访时有髓鞘再生证据的患者基线可溶性Tyro3（p = 0.033）和Gas6（p = 0.014）较低。除Mer外，RRMS患者中Gas6/TAM浓度在治疗后未发生变化。
我们的数据表明Gas6/TAM受体系统在影响脱髓鞘和无效髓鞘再生的神经退行性变过程中可能发挥作用。
