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Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. doi: 10.1016/j.stemcr.2018.01.031. Epub 2018 Mar 1.

Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.

Author information

1
Department of Pathology, University of Washington, Seattle, WA 98109, USA; Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: jeyoung@uw.edu.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA.
3
Department of Pathology, University of Washington, Seattle, WA 98109, USA; Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
4
Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, New York, NY 10021, USA.
5
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY 10032, USA.
6
Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, CA 92093, USA. Electronic address: lgoldstein@ucsd.edu.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; human induced pluripotent stem cells; retromer complex stabilization

PMID:
29503090
PMCID:
PMC5919412
DOI:
10.1016/j.stemcr.2018.01.031
[Indexed for MEDLINE]
Free PMC Article

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