In a recent study published in Nature Communications, researchers from Genentech and the University of California, San Francisco have created a human cellular model of Alzheimer’s Disease (AD) in a dish.
Despite over 40 years of intense research efforts no effective treatment for AD exists, causing many scientists to question the suitability of research models used and cast doubt on the Amyloid Hypothesis.
Now scientists from Genentech and UCSF have created a high-throughput screening model of AD by co-culturing large numbers (100-200 million) of human iPSC-derived neurons, astrocytes and microglia in 384 well plates in an automated fashion over a long period of time. Their study showed that long-term, automated co-culture of iPSC cells to create a model of neurodegenerative disease is possible and successfully recapitulates the hallmarks of human AD pathology, such as: severe synapse loss, induction of phosphorylated-Tau in neurons and their subsequent cell death, beta-amyloid (Aβ) plaque formation and activated microglia.
Using this co-culture model, Bassill et al. initially tested their model by adding soluble Aβ oligomers to the wells. They discovered that the level of pathological response in the wells correlated with the concentration of soluble Aβ added, as higher concentrations of soluble Aβ induced greater pathology, faster.
Aβ induced neurodegeneration. a, b) Differentiated NAG neurons (12 weeks+) show loss of dendrites (MAP2, green) and cell bodies (CUX2, red) when treated with soluble Aβ species for 7 days (b) in comparison to no treatment condition (a). c) Anti-Aβ antibody co-treatment with soluble Aβ species blocks Aβ-induced cell death. Scale bar 50 μm. Credit: Bassill et al. (2021)
They then took their impressive findings a step further and successfully used their model for a small drug-screen to validate the utility of their model and associated assays. This was before exploring the effect of anti-Aβ antibodies on AD progression in their system confirming that progress of the disease pathology could be slowed in their model. And, this validation could be done in a high-throughput fashion using their set up.
Taken together, this paper achieves several things:
1. It shows the group have devised a high-throughput, automated method to recapitulate neurodegenerative diseases using human iPSC-derived brain cells. Their findings showcase the power of iPSC technology in assay development and R&D to advance both our understanding of #Alzheimers Disease and drug discovery efforts.
2. Using this method, they uncovered new insights to Alzheimer’s Disease pathology and the interaction between neurons, astrocytes and microglia.
3. It highlights the power of co-culturing human iPSCs to create physiologically relevant disease models that will greatly advance our understanding of disease and lead to better design and translation of therapeutics.
At Axol we’re excited see that our cells are being utilised in innovative studies like this where models that recapitulate neurodegenerative disease can be used to create clinical trials in the dish and lead to better translation of therapeutics into first-in-human trials, and hopefully accelerate therapeutic development