Efficient in vitro screening platforms are essential for accelerating drug discovery in Alzheimer’s and Parkinson’s disease. Presented at AD/PD 2024 in Lisbon and updated for AD/PD 2025 in Vienna, this poster from our Belgium neurology team presents validated microglial (HMC3) and differentiated neuronal-like (SH-SY5Y) cell models designed to recapitulate key hallmarks of neurodegeneration. 

Using preformed amyloid beta (Aβ-42) and alpha-synuclein (αSyn) fibrils, the platform models fibril aggregation kinetics, neurotoxicity, reactive oxygen species (ROS) production, and phagocytic activity, validated against clinical reference compounds Edaravone and Aducanumab. These reproducible assays provide a cost-effective, higher-throughput approach to compound prioritization prior to in vivo progression — a practical mechanistic filter for Alzheimer’s and Parkinson’s disease drug discovery programs. 

Alzheimer’s and Parkinson’s disease drug development is held back due to the lack of in vitro reproducible models representing human complexity for screening disease-modifying therapeutics inexpensively, efficiently, and rapidly. Here, we present validated cellular models to enable efficient screening of disease-modifying candidate compounds for Alzheimer’s and Parkinson’s diseases prior to, or in conjunction with, in vivo screening. 

Microglial (HMC3) and differentiated neuronal-like (SH-SY5Y) cells were treated with preformed amyloid beta (Aβ-42) or alpha-synuclein (αSyn) fibrils. Common neurodegeneration hallmarks — aggregation, neurotoxicity, ROS production, and phagocytosis — were modelled using validated assay formats. Supplementary data further demonstrate αSyn-specific and glutamate-induced neurotoxicity assays. 

Aβ-42 fibril aggregation kinetics were confirmed by Thioflavin-T fluorescence assay. Fibrillar Aβ-42 and αSyn induced cell toxicity in both neuronal and microglial cells. Aβ fibrils induced ROS production in SH-SY5Y cells, rescued by Edaravone co-treatment. In HMC3 cells, Aβ-42 fibril treatment induced increased phagocytic capacity, further elevated upon Aducanumab co-treatment. 

These cellular models serve as a highly efficient tool for compound screening before in vivo progression, providing target-specific mechanistic insights with higher throughput capabilities than animal disease models.