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Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's
Rik van der Kant1, Vanessa F Langness2, Cheryl M Herrera2
1Department 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.
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.
Insights
Altered cholesterol metabolism, specifically cholesteryl esters (CE), influences Alzheimer's disease (AD) pathology by regulating Tau and amyloid-beta (Aβ) via independent pathways. Targeting CYP46A1 may offer a therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Alzheimer's disease (AD) predisposition is linked to cholesterol metabolism.
- Molecular pathways connecting cholesterol to AD phenotypes require further elucidation.
Purpose of the Study:
- To identify upstream regulators of Tau accumulation in Alzheimer's disease (AD).
- To investigate the role of cholesteryl esters (CE) in AD pathogenesis.
- To explore potential therapeutic targets for AD.
Main Methods:
- Phenotypic screening of pTau accumulation in patient-derived induced pluripotent stem cell (iPSC) neurons.
- Utilizing isogenic iPSC lines with mutations in APP.
- Assessing the effects of CE on Tau and amyloid-beta (Aβ) secretion.
- Screening for efficacy and toxicity of CYP46A1 activation in iPSC-derived astrocytes and neurons.
Main Results:
- Cholesteryl esters (CE) were identified as upstream regulators of Tau in early AD development.
- CE independently regulate Tau and Aβ secretion through distinct pathways.
- Allosteric activation of CYP46A1 reduces neuronal CE levels with good tolerability in astrocytes.
Conclusions:
- Cholesteryl esters (CE) play a significant role in Alzheimer's disease (AD) pathology, independently affecting Tau and Aβ.
- A druggable axis involving CYP46A1, CE, and Tau presents a potential therapeutic avenue for AD.