A Polymer Matrix-Supported 3D Co-culture Model Recapitulating Amyloid-β Accumulation for Alzheimer’s Drug Screening

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathological accumulation and aggregation of amyloid beta. Although anti-amyloid therapeutics have emerged as disease-modifying treatments for AD, in vitro models capable of reproducing sustained amyloid accumulation while evaluating drug responses remain limited. In conventional two-dimensional culture systems, amyloid beta can be readily lost during medium exchange or washing procedures, making it difficult to maintain a stable amyloid-rich environment over time.
Here, we developed a hydrogel-based three-dimensional co-culture model composed of neuron-like SH-SY5Y cells and macrophage-like THP-1 cells. To establish sustained amyloid beta production, both cell types were engineered to express mRNA encoding the amyloid beta sequence. The hydrogel matrix was designed to reduce the diffusion and physical loss of amyloid beta and promote its local accumulation, thereby providing a more stable environment for reproducing amyloid beta aggregation than conventional liquid-based culture systems.
The established three-dimensional co-culture model was treated with lecanemab, an anti-amyloid monoclonal antibody. Drug-induced responses were evaluated by comparing amyloid beta levels and cellular responses before and after treatment.
The developed hydrogel-based three-dimensional co-culture model enables the evaluation of anti-amyloid therapeutics under conditions that reproduce sustained amyloid beta accumulation and aggregation. This platform may serve as an in vitro drug-screening tool for the comparative assessment of candidate therapeutics for Alzheimer’s disease.