Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease,Acta Neuropathologica Communications

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Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2021-08-23 , DOI: 10.1186/s40478-021-01245-z
Charysse Vandendriessche _{1,

2} , Sriram Balusu ₃ , Caroline Van Cauwenberghe _{1,

2} , Marjana Brkic _{1,

2,

4} , Marie Pauwels _{1,

2} , Nele Plehiers _{1,

2} , Arnout Bruggeman _{1,

2,

5} , Pieter Dujardin _{1,

2} , Griet Van Imschoot _{1,

2} , Elien Van Wonterghem _{1,

2} , An Hendrix _{6,

7} , Femke Baeke _{1,

2,

8} , Riet De Rycke _{1,

2,

8} , Kris Gevaert _{9,

10} , Roosmarijn E Vandenbroucke _{1,

2}

Affiliation

Increasing evidence indicates that extracellular vesicles (EVs) play an important role in the pathogenesis of Alzheimer’s disease (AD). We previously reported that the blood–cerebrospinal fluid (CSF) interface, formed by the choroid plexus epithelial (CPE) cells, releases an increased amount of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-mediated EV release in AD pathogenesis. We observed increased EV levels in the CSF of young transgenic APP/PS1 mice which correlated with high amyloid beta (Aβ) CSF levels at this age. The intracerebroventricular (icv) injection of Aβ oligomers (AβO) in wild-type mice revealed a significant increase of EVs in the CSF, signifying that the presence of CSF-AβO is sufficient to induce increased EV secretion. Using in vivo, in vitro and ex vivo approaches, we identified the CP as a major source of the CSF-EVs. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures. Proteome analysis of these EVs revealed the presence of several pro-inflammatory proteins, including the complement protein C3. Strikingly, inhibition of EV production using GW4869 resulted in protection against acute AβO-induced cognitive decline. Further research into the underlying mechanisms of this EV secretion might open up novel therapeutic strategies to impact the pathogenesis and progression of AD.

中文翻译：

血脑脊液界面细胞外囊泡分泌在阿尔茨海默病发病机制中的重要性

越来越多的证据表明，细胞外囊泡 (EVs) 在阿尔茨海默病 (AD) 的发病机制中发挥着重要作用。我们之前报道过，由脉络丛上皮 (CPE) 细胞形成的血液-脑脊液 (CSF) 界面会向 CSF 中释放更多的 EV，以响应外周炎症。在这里，我们研究了 CP 介导的 EV 释放在 AD 发病机制中的重要性。我们观察到年轻转基因 APP/PS1 小鼠脑脊液中 EV 水平升高，这与这个年龄的高淀粉样蛋白 β (Aβ) 脑脊液水平相关。在野生型小鼠中脑室内 (icv) 注射 Aβ 寡聚体 (AβO) 显示 CSF 中的 EV 显着增加，这表明 CSF-AβO 的存在足以诱导 EV 分泌增加。使用体内、体外和离体方法，我们将 CP 确定为 CSF-EV 的主要来源。有趣的是，AβO 诱导的 CP 衍生 EV 在混合皮质培养物中诱导促炎作用。这些 EV 的蛋白质组分析显示存在几种促炎蛋白，包括补体蛋白 C3。引人注目的是，使用 GW4869 抑制 EV 产生可防止急性 AβO 诱导的认知衰退。进一步研究这种 EV 分泌的潜在机制可能会开辟新的治疗策略来影响 AD 的发病机制和进展。使用 GW4869 抑制 EV 产生可防止急性 AβO 诱导的认知衰退。进一步研究这种 EV 分泌的潜在机制可能会开辟新的治疗策略来影响 AD 的发病机制和进展。使用 GW4869 抑制 EV 产生可防止急性 AβO 诱导的认知衰退。进一步研究这种 EV 分泌的潜在机制可能会开辟新的治疗策略来影响 AD 的发病机制和进展。

更新日期：2021-08-23

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