Stem cell-based models to study the role of microglia, and mutations in TREM2, as well as astrocytes, in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the presence of plaques, tangles, en neuroinflammation in the brain. Although many research is already done, no cure exists. In my research, I will aim at develping an in vitro model to study AD. There are indeed some mouse models but they do not mimic the whole human pathology. So there is need to develop a model that shows all the hallmarks of AD. This can be used as a drug screening tool but also to study other neurodegenerative diseases as neuroinflammation is seen in all of them. Another important factor that need to be studied is the effect of TREM2, found on microglia and monocytes, on clearance of plaques/tangles and inflammation. I will develop a model to study TREM2 and the neuroinflammation involved by impaired functioning of this surface receptor by creating three tools and combining these in the final working plan. The first tool is to get a protocol to derive microglia form hPSCs. This will be done based on the knowledge that microglia are derived form the primitive pathway, that the Wnt-pathway need to be inhibited, and that survival and differentiation is dependent on signaling of IL34 and CSF1. The same differentiation protocol will be applied on a cell line that contains a mutation in TREM2 that was shown to increase the risk for AD and a cell line that is knock out for TREM2. The second tool is to get neurons that produce plaques and tangles. This will be achieved by genome editing cell lines by introducing a cassette that contains the mutated APP and PS1 genes. The same cassette will also be introduced in a cell line that already contains three mutations in the tau protein. Neurons derived from this cell line are hypothesized to produce not only plaques but also tangles. Togehter with an impaired or lost TREM2 function on microglia this is hypothesized to enhance inflammation. The third tool is to mimic the environment of the brain as a culture environment for the microglia and neurons. This will be achieved by designing a PEG-hydrogel that is enriched with ECM components found in the brain. These microlgia en neurons will be co-cultured in the hydrogel in the last working plan where I will see all the hallmarks seen in AD. This will give me the model to study AD.

Publication year:2021

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