Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons
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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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Lipid droplets rich in cholesterol esters drive the accumulation of phosphorylated tau in iPSC-derived neurons.
“LDs rich in cholesterol esters drive the accumulation of phosphorylated tau in iPSC-derived neurons (van der Kant et al., 2019).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as van der Kant et al., 2019
The Results section, “The Effect of Statins on pTau Is Mediated by Cholesteryl Esters” (page unavailable), reports that cholesteryl esters regulate phosphorylated tau levels in human iPSC-derived familial Alzheimer’s neurons. The Discussion, “Pathways that Mediate the Effect of CE on pTau and Aβ” (page unavailable), identifies lipid droplets as cholesteryl-ester storage sites, but does not establish that the droplets themselves drive tau accumulation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLipids are central to AD pathogenesis, as suggested by studies showing cholesterol dysregulation in a range of AD models and patients' brains.
“Together with studies showing cholesterol dysregulation in a range of AD models and patients’ brains, these studies suggest lipids are central to AD pathogenesis14–18.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [15]
Elevated CE levels have been reported in AD brains and AD models.
“Elevated CE levels have been reported in AD brains as well as AD models12,14,15.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [15]
CE is upregulated in AD patient brain and various AD models, and its downregulation is protective in various AD models.
“based on its upregulation in AD patient brain and various AD models, along with the fact that its downregulation is protective in various AD models10,12,15,64.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [15]
A reduction of tau through proteostatic mechanisms cannot be ruled out as a cause of the phosphorylation decrease, but the continued rise in t-tau suggests it is probably not the cause for the falling phosphorylation rate at some sites.
“A reduction of tau through proteostatic mechanisms cannot be excluded54 as a cause for the decrease in phosphorylation, but the continued increase of t-tau (Supplementary Fig. 3) would suggest that this is probably not the cause for the decreasing rate of phosphorylation for some sites.”
From A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease (2020) · cites this paper as [54]
For studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and complement isogenic iPSC strategies.
“Collectively, for studying age-related vulnerability and mechanisms relevant to AD, iNs have advantages over iPSC models and thus complement isogenic iPSC strategies (van der Kant et al., 2019; Meyer et al., 2019; Woodruff et al., 2013).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as van der Kant et al., 2019
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Lipid and Lipoprotein Metabolism in Microglia
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Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
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Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
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Recent advances in metabolomics analysis for early drug development.
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The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking
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APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
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“12,14,15 To explore if ApoE isoforms can differentially modulate CE uptake, we pre-complexed BODIPY-conju-gated CE (BODIPY-CE) with HDL in the presence or absence of ApoE, then treated H4 cells with the complex.”
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Cholesterol Metabolism in Aging and Age-Related Disorders
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Remembering your A, B, C's: Alzheimer's disease and ABCA1
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Role of the Lipid Membrane and Membrane Proteins in Tau Pathology
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The future of stem cell therapies of Alzheimer’s disease
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“Moreover, mitigation of cholesterol imbalances has been increasingly explored as a therapeutic strategy, with success in pre-clinical models of AD [22, 23].”
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Cholesterol determines the cytosolic entry and seeded aggregation of tau
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Alzheimer’s disease pathogenesis: standing at the crossroad of lipid metabolism and immune response
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ER‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein
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From beta amyloid to altered proteostasis in Alzheimer’s disease
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Leading the way in the nervous system: Lipid Droplets as new players in health and disease
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Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol
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Assessment of cholesterol homeostasis in the living human brain
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The multifaceted role of WNT signaling in Alzheimer’s disease onset and age-related progression.
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Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery
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Tau Related Pathways as a Connecting Link between Epilepsy and Alzheimer’s Disease
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Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization
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The silence of the fats: A MAM’s story about Alzheimer
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Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease
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Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases
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Synapses, Microglia, and Lipids in Alzheimer’s Disease
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The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease
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Modeling Alzheimer’s disease with human iPS cells: advancements, lessons, and applications
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Lipid metabolism of leukocytes in the unstimulated and activated states
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Stem Cell Therapy for Alzheimer’s Disease: A Scoping Review for 2017–2022
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Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease
Nanjundaiah, S., Chidambaram, H., Chandrashekar, M., & Chinnathambi, S. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00883-6 · Cited by 36 · see citing works
Targeting epigenetics: A novel promise for Alzheimer’s disease treatment
Jeremic, D., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102003 · Cited by 36 · see citing works
Contribution of Membrane Lipids to Postsynaptic Protein Organization
Westra, M., Gutiérrez, Y., & MacGillavry, H. D. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.790773 · Cited by 35 · see citing works
- Authors
- van der Kant, R., Langness, V. F., Herrera, C. M., Williams, D. A., Fong, L. K., Leestemaker, Y., Steenvoorden, E., Rynearson, K. D., Brouwers, J. F., Helms, J. B., Ovaa, H., Giera, M., Wagner, S. L., Bang, A. G., & Goldstein, L. S. B.
- Affiliations
- University of California San Diego (US)
- Leiden University Medical Center (NL)
- Utrecht University (NL)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Goldstein, Lawrence S.B.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 24
- Issue
- 3
- Pages
- 363-375.e9
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6414424
- OpenAlex
- W2914222102
- Cited by
- 350
- References
- 74
- Citations by year
- 2026: 30 · 2025: 48 · 2024: 57 · 2023: 56 · 2022: 45 · 2021: 49 · 2020: 41 · 2019: 23 · 2018: 1
- FWCI
- 26.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell stem cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Alzheimer Netherlands (WE.15-2013-01)
- ERC Marie Curie (622444, APPtoTau)
- NIH (5T32AG000216-24)
- NIA (1RF1AG048083-01)
- CIRM (RB5-07011)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- Alzheimer's disease, cholesterol metabolism, cholesterol esters, tau phosphorylation, amyloid-beta secretion, CYP46A1, iPSC-derived neurons, APP mutations, astrocytes, therapeutic target, phenotypic screening
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Cholesterol, Mice, Inbred C57BL, Neurons, Amyloid beta-Peptides, tau Proteins, Mice, Induced Pluripotent Stem Cells
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