<br>在阿尔茨海默病中，细胞外 CIRP 通过 TREM-1 诱导神经毒性 A1 星形胶质细胞,Alzheimer's & Dementia

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在阿尔茨海默病中，细胞外 CIRP 通过 TREM-1 诱导神经毒性 A1 星形胶质细胞
Alzheimer's & Dementia ( IF 13.0 ) Pub Date : 2025-01-09 , DOI: 10.1002/alz.094835
Archna Sharma ₁ , Dilara Aylar ₁ , Yongchan Lee ₁ , Max Brenner ₁ , Philippe Marambaud ₁ , Ping Wang ₁

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背景虽然 A1 星形胶质细胞在阿尔茨海默病（AD）中也有报道，但潜在的分子机制很复杂，仍然难以捉摸。促炎细胞外冷诱导 RNA 结合蛋白（eCIRP）由小胶质细胞响应 AD 相关神经元淀粉样蛋白 β 释放。eCIRP 激活髓系细胞 1 （TREM-1）上表达的触发受体。因此，我们假设由于炎症应激导致 AD 中 eCIRP 水平升高通过星形胶质细胞 TREM-1 诱导 A1.方法ELISA 在 AD 患者的脑脊液（CSF;内部阿尔茨海默病中心存储库）或血浆（Precision Biospecimen Solutions， Bethesda， MD）或 hTau.P301S 小鼠（Michel Goedert 博士，英国剑桥）血浆中进行。用 eCIRP 刺激来自小抗 CIRP 肽 M3 的 C57BL/6 小鼠± C8-D1a 细胞（ATCC）或磁性纯化的原代星形胶质细胞。C57BL/6 小鼠脑室内（icv）注射 eCIRP。通过 qPCR 定量 mRNA 的表达，通过免疫印迹定量蛋白质，并通过 ELISA 或 R&D 蛋白质组分析仪释放水平。两组分析采用学生 t 检验，多组分析采用单因素方差分析（ANOVA）-SNK 检验，相关性采用 Spearman's-Rho 分析，如果 p < 0.05.结果AD 患者脑脊液和血浆中 eCIRP 水平升高，hTau.P301S 小鼠血浆中 eCIRP 水平升高，血浆 eCIRP 与 AD 患者星形胶质细胞活化标志物胶质纤维酸性蛋白（GFAP）密切相关（图 1）。eCIRP 强烈诱导 C8-D1a 细胞、原代星形胶质细胞和注射 icv eCIRP 的小鼠大脑中的 A1 星形胶质细胞特异性基因和星形胶质细胞释放促炎因子和神经毒性因子。特别是，eCIRP 增加了补体 3，补体 3 是一种参与神经炎症相关神经变性的 A1 星形胶质细胞标志物。来自 TREM-1 敲除小鼠的原代星形胶质细胞对 A1 星形胶质细胞的 eCIRP 诱导耐药。此外，暴露于 eCIRP 的星形胶质细胞具有更高的 TREM-1 总蛋白和表面蛋白水平，增加 Syk 磷酸化，并上调 NFκB mRNA。重要的是，M3 有效抑制了 eCIRP 对 A1 星形胶质细胞的诱导及其对促炎和神经毒性介质的释放。结论总的来说，我们的数据提供了 eCIRP 与 AD 患者星形胶质细胞反应性的强相关性，确定了 eCIRP 通过 TREM-1 诱导 A1 星形胶质细胞的新分子机制和 eCIRP 诱导的 A1 星形胶质细胞的 M3 肽衰减。这些发现指出了 AD 中靶向神经毒性 A1 星形胶质细胞的新型治疗机会。

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Extracellular CIRP induces neurotoxic A1 astrocytes via TREM‐1 in Alzheimer’s disease

BackgroundWhile A1 astrocytes are reported in Alzheimer’s disease (AD), the underlying molecular mechanisms are complex and remain elusive. Proinflammatory extracellular cold‐inducible RNA‐binding protein (eCIRP) is released by microglia in response to AD‐associated neuronal amyloid‐β. eCIRP activates the triggering receptor expressed on myeloid cells‐1 (TREM‐1). Thus, we hypothesized that increased levels of eCIRP in AD due to inflammatory stress induce A1 via astrocytic TREM‐1.MethodELISA was performed in the AD patients’ cerebrospinal fluid (CSF; in‐house Alzheimer’s Disease Center repository) or plasma (Precision Biospecimen Solutions, Bethesda, MD) or hTau.P301S mice (Dr. Michel Goedert, Cambridge, UK) plasma. C8‐D1a cells (ATCC) or magnetically purified primary astrocytes, from C57BL/6 mice ± small anti‐CIRP peptide M3 or from TREM1‐KO mice, were stimulated with eCIRP. C57BL/6 mice were injected intracerebroventricular (icv) with eCIRP. Expression of mRNA was quantified by qPCR, protein by immunoblotting and released levels by ELISA or R&D proteome profiler. Student’s t‐test was used for two‐group analysis, one‐way analysis of variance (ANOVA)‐SNK test for multigroup analysis, and Spearman’s‐Rho analysis for correlations, with significance if p < 0.05.ResultLevels of eCIRP were elevated in the CSF and plasma of AD patients, in hTau.P301S mice, and plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients (Fig. 1). eCIRP strongly induced A1 astrocyte‐specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8‐D1a cells, primary astrocytes and icv eCIRP‐injected mice brains. In particular, eCIRP increased Complement 3, an A1 astrocytic marker involved in neuroinflammation‐associated neurodegeneration. Primary astrocytes from TREM‐1 knockout mice were resistant to eCIRP induction of A1 astrocytes. Moreover, astrocytes exposed to eCIRP had higher TREM‐1 total and surface protein levels, increased Syk phosphorylation, and upregulated NFκB mRNA. Importantly, M3 effectively inhibited eCIRP’s induction of A1 astrocytes and their release of proinflammatory and neurotoxic mediators.ConclusionCollectively, our data provides a strong correlation of eCIRP with astrocyte reactivity in AD patients, identifies a novel molecular mechanism by which eCIRP induces A1 astrocytes via TREM‐1 and M3 peptide attenuation of eCIRP‐induced A1 astrocytes. These findings point to a novel therapeutic opportunity targeting neurotoxic A1 astrocytes in AD.

更新日期：2025-01-09

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