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Cell Stem Cell. 2019 Jan 16. pii: S1934-5909(18)30603-9. doi: 10.1016/j.stem.2018.12.013. [Epub ahead of print]

Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
4
Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
5
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University Yalelaan 2, 3584 CM Utrecht, the Netherlands.
7
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Research Biologist, VA San Diego Healthcare System, La Jolla, CA 92161, USA.
8
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
9
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: lgoldstein@ucsd.edu.

Abstract

Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer's disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated by independent pathways. Efficacy and toxicity screening in iPSC-derived astrocytes and neurons showed that allosteric activation of CYP46A1 lowers CE specifically in neurons and is well tolerated by astrocytes. These data reveal that CE independently regulate Tau and Aβ and identify a druggable CYP46A1-CE-Tau axis in AD.

KEYWORDS:

Alzheimer’s disease; CYP46A1 Tau; amyloid beta; cholesterol metabolism; cholesteryl esters; disease modeling; drug screening; induced pluripotent stem cells; lipids; proteostasis

PMID:
30686764
DOI:
10.1016/j.stem.2018.12.013
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