Alzheimer’s disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyperactivation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform. Our model provided key representative AD features: beta-amyloid aggregation, phosphorylated tau accumulation,
and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage, and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural–glial interactions and drug discovery.
研究取得以下结果:
1. 依托微流体平台建立人类AD三体系统(神经元+星形胶质细胞+小胶质细胞)Generation of human AD triculture system (Neu+AC+MG AD)
using a microfluidic platform
该系统具备AD特征性改变:
增加可溶性Aβ,炎性细胞因子/趋化因子和p-tau(Increased soluble Aβ, inflammatory cytokines/chemokines, and p-tau);
诱导小胶质细胞迁移,表型改变和促炎因子的分泌(induced microglial migration, phenotype changes, and secretion of pro-inflammatory factors);
以及进一步证明:
招募的小胶质细胞对AD神经元和星形胶质细胞有毒(Recruited microglia are toxic to AD neurons and astrocytes);
招募的小胶质细胞通过IFN-γ和TLR4依赖性机制诱导神经元损失(Recruited microglia induced neuronal loss through a IFN-γ and TLR4-dependent mechanism);
敲低TLR4表达提供了针对神经毒性小胶质细胞激活的保护作用(Knocking down TLR4 expression provided protection against neurotoxic microglial activation);
人iPSC衍生的AD Neu + AC在三体培养中复制小胶质细胞募集,激活和Neu + AC死亡(Human iPSC-derived AD Neu+AC replicate microglial recruitment, activation, and Neu+AC death in triculture)。
以上文字由北京国仁医院特聘会诊专家徐俊教授整理,文章来源:神经医学