Monomeric and oligomeric amyloid-β cause distinct Alzheimer's disease pathophysiological characteristics in astrocytes in human glymphatics-on-chip models,Lab on a Chip

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Monomeric and oligomeric amyloid-β cause distinct Alzheimer's disease pathophysiological characteristics in astrocytes in human glymphatics-on-chip models
Lab on a Chip ( IF 6.1 ) Pub Date : 2024-07-16 , DOI: 10.1039/d4lc00287c
Aria R Yslas ₁ , Rena Park ₁ , Nozomi Nishimura ₁ , Esak Lee ₁

Affiliation

Alzheimer's disease (AD) is marked by the aggregation of extracellular amyloid-β (Aβ) and astrocyte dysfunction. For Aβ oligomers or aggregates to be formed, there must be Aβ monomers present; however, the roles of monomeric Aβ (mAβ) and oligomeric Aβ (oAβ) in astrocyte pathogenesis are poorly understood. We cultured astrocytes in a brain-mimicking three-dimensional (3D) extracellular matrix and revealed that both mAβ and oAβ caused astrocytic atrophy and hyper-reactivity, but showed distinct Ca²⁺ changes in astrocytes. This 3D culture evolved into a microfluidic glymphatics-on-chip model containing astrocytes and endothelial cells with the interstitial fluid (ISF). The glymphatics-on-chip model not only reproduced the astrocytic atrophy, hyper-reactivity, and Ca²⁺ changes induced by mAβ and oAβ, but recapitulated that the components of the dystrophin-associated complex (DAC) and aquaporin-4 (AQP4) were properly maintained by the ISF, and dysregulated by mAβ and oAβ. Collectively, mAβ and oAβ cause distinct AD pathophysiological characteristics in the astrocytes.

中文翻译：

单体和寡聚淀粉样蛋白-β在人类类淋巴芯片模型中的星形胶质细胞中引起不同的阿尔茨海默氏病病理生理学特征

阿尔茨海默病 (AD) 的特点是细胞外淀粉样蛋白-β (Aβ) 聚集和星形胶质细胞功能障碍。为了形成 Aβ 寡聚体或聚集体，必须存在 Aβ 单体；然而，人们对单体 Aβ (mAβ) 和寡聚 Aβ (oAβ) 在星形胶质细胞发病机制中的作用知之甚少。我们在模拟大脑的三维 (3D) 细胞外基质中培养星形胶质细胞，发现 mAβ 和 oAβ 都会导致星形胶质细胞萎缩和高反应性，但在星形胶质细胞中显示出明显的 Ca ²⁺变化。这种 3D 培养物演变成包含星形胶质细胞和内皮细胞以及间质液 (ISF) 的微流体芯片上淋巴管模型。芯片上的类淋巴管模型不仅再现了 mAβ 和 oAβ 诱导的星形胶质细胞萎缩、高反应性和 Ca ²⁺变化，而且概括了抗肌营养不良蛋白相关复合物 (DAC) 和水通道蛋白-4 (AQP4) 的组成部分由 ISF 适当维持，并由 mAβ 和 oAβ 失调。总的来说，mAβ 和 oAβ 在星形胶质细胞中引起不同的 AD 病理生理特征。

更新日期：2024-07-16

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