Abstract
Advancement in human induced pluripotent stem cell (iPSC) neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells. However, iPSC differentiation and culturing protocols have posed challenges to maintaining consistency. Here, we generated an automated, consistent, and long-term culturing platform of human iPSC neurons, astrocytes, and microglia. Using this platform we generated a iPSC AD model using human derived cells, which showed signs of Aβ plaques, dystrophic neurites around plaques, synapse loss, dendrite retraction, axon fragmentation, phospho-Tau induction, and neuronal cell death in one model. We showed that the human iPSC microglia internalized and compacted Aβ to generate and surround the plaques, thereby conferring some neuroprotection. We investigated the mechanism of action of anti-Aβ antibodies protection and found that they protected neurons from these pathologies and were most effective before pTau induction. Taken together, these results suggest that this model can facilitate target discovery and drug development efforts.
Highlights
Advancement in human induced pluripotent stem cell neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells
We have generated a human induced pluripotent stem cell (iPSC) Alzheimer’s disease (AD) model comprised of human neurons, astrocytes, and microglia
In this high-throughput triple culture system, the addition of soluble Aβ42 species recapitulated the hallmarks of AD and developed in a sequential order of events that is similar to human AD disease progression
Summary
Advancement in human induced pluripotent stem cell (iPSC) neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells. We investigated the mechanism of action of anti-Aβ antibodies protection and found that they protected neurons from these pathologies and were most effective before pTau induction Taken together, these results suggest that this model can facilitate target discovery and drug development efforts. The amyloid hypothesis proposes that abnormally folded Aβ peptides initiate a causal cascade beginning with Aβ oligomer aggregation into plaques, which trigger Tau hyperphosphorylation and neurofibrillary tangle formation, resulting in neuronal cell death[12,13]. This hypothesis has been the theoretical foundation for the generation of numerous animal models, diagnostics, and drug development programs for AD12. The recent failures of many anti-Aβ therapeutics have led some in the field to cast some doubt on the amyloid hypothesis[18,19,20]
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