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

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

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)363-375.e9
JournalCell Stem Cell
Volume24
Issue number3
Early online date16 Jan 2019
DOIs
Publication statusPublished - 7 Mar 2019

Fingerprint

Induced Pluripotent Stem Cells
Cholesterol Esters
Amyloid
Alzheimer Disease
Cholesterol
Neurons
Astrocytes
Molecular Biology
Alleles
Phenotype
Cell Line
Mutation

Keywords

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

Cite this

van der Kant, Rik ; Langness, Vanessa F ; Herrera, Cheryl M ; Williams, Daniel A ; Fong, Lauren K ; Leestemaker, Yves ; Steenvoorden, Evelyne ; Rynearson, Kevin D ; Brouwers, Jos F ; Helms, J Bernd ; Ovaa, Huib ; Giera, Martin ; Wagner, Steven L ; Bang, Anne G ; Goldstein, Lawrence S B. / Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. In: Cell Stem Cell. 2019 ; Vol. 24, No. 3. pp. 363-375.e9.
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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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van der Kant, R, Langness, VF, Herrera, CM, Williams, DA, Fong, LK, Leestemaker, Y, Steenvoorden, E, Rynearson, KD, Brouwers, JF, Helms, JB, Ovaa, H, Giera, M, Wagner, SL, Bang, AG & Goldstein, LSB 2019, 'Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons' Cell Stem Cell, vol. 24, no. 3, pp. 363-375.e9. https://doi.org/10.1016/j.stem.2018.12.013

Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. / van der Kant, Rik; Langness, Vanessa F; Herrera, Cheryl M; Williams, Daniel A; Fong, Lauren K; Leestemaker, Yves; Steenvoorden, Evelyne; Rynearson, Kevin D; Brouwers, Jos F; Helms, J Bernd; Ovaa, Huib; Giera, Martin; Wagner, Steven L; Bang, Anne G; Goldstein, Lawrence S B.

In: Cell Stem Cell, Vol. 24, No. 3, 07.03.2019, p. 363-375.e9.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons

AU - van der Kant, Rik

AU - Langness, Vanessa F

AU - Herrera, Cheryl M

AU - Williams, Daniel A

AU - Fong, Lauren K

AU - Leestemaker, Yves

AU - Steenvoorden, Evelyne

AU - Rynearson, Kevin D

AU - Brouwers, Jos F

AU - Helms, J Bernd

AU - Ovaa, Huib

AU - Giera, Martin

AU - Wagner, Steven L

AU - Bang, Anne G

AU - Goldstein, Lawrence S B

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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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KW - amyloid beta

KW - cholesterol metabolism

KW - cholesteryl esters

KW - disease modeling

KW - drug screening

KW - induced pluripotent stem cells

KW - lipids

KW - proteostasis

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