Journal
STEM CELL REPORTS
Volume 10, Issue 3, Pages 1046-1058Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.01.031
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Funding
- BrightFocus Foundation
- Tietze Foundation
- ADRC (NIH) [AG005136]
- University of Washington (UW)
- Ellison Foundation
- NIH: NIH-NIA [2P50AG005131-31]
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Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system.
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