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

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Jan 29

PMID 30686764

Citations 164

Authors

Rik van der Kant

Vanessa F Langness

Cheryl M Herrera

Daniel A Williams

Lauren K Fong

Yves Leestemaker

Evelyne Steenvoorden

Kevin D Rynearson

Jos F Brouwers

J Bernd Helms

Huib Ovaa

Martin Giera

Steven L Wagner

Anne G Bang

Lawrence S B Goldstein

Affiliations

Soon will be listed here.

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.

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