. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9. Epub 2019 Jan 24 PubMed.

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  1. In this elegant work, van der Kant et al. performed a drug screen on hiPSC-derived AD neurons and identified, among others, four statins able to significantly decrease p-tau accumulation by reducing the levels of cholesteryl esters (CE). Interestingly, the same effect was mimicked by efavirenz, an allosteric activator of CYP46A1. The authors also found that while the effects of lowering CE on p-tau is mediated by the proteasome, the effect of CE on Aβ42 is mediated by the cholesterol-binding domain in APP.

    This study highlights once again the importance of CYP46A1 and cholesterol turnover through the mevalonate pathway in the brain (Kotti et al., 2006). The findings are certainly in line with previous studies where activation of CYP46A1 in hippocampi of AD mice reduced Aβ plaques and restored spatial memory performances (Hudry et al., 2010), while inhibition of CYP46A1 in tau mice led to increased tau phosphorylation (Djelti et al., 2015). Treatment with low doses of efavirenz in AD mice also led to positive effects on Aβ reduction (Mast et al., 2017). 

    Altogether, targeting cholesterol metabolism may become a viable therapeutic approach for AD and other neurodegenerative diseases.

    References:

    . Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74. PubMed.

    . Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther. 2010 Jan;18(1):44-53. PubMed.

    . CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease. Brain. 2015 Aug;138(Pt 8):2383-98. Epub 2015 Jul 2 PubMed.

    . Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1). PLoS One. 2017;12(10):e0187168. Epub 2017 Oct 26 PubMed.

    View all comments by Silvia Maioli
  2. Intraneuronal cholesterol dyshomeostasis at the crossroad between tau abnormal phosphorylation and amyloid-β secretion

    This article by van der Kant and colleagues in Cell Stem Cell proposes that intraneuronal cholesterol dyshomeostasis could be an early trigger for both amyloidosis and tau pathological changes, albeit through distinct cascades of events. It is true that the link between cholesterol metabolism and Alzheimer’s disease (AD) has oftentimes been highlighted in epidemiological or experimental studies, but so far the exact underlying mechanisms have eluded investigations of human neuronal cells. Using an unbiased screen of over 1,600 FDA-approved and preclinical compounds in iPSC-derived neurons, the authors identified several statins as potent inhibitors of phospho-tau accumulation (across several tau phospho-epitopes and independent iPSC lines), an effect sustained after APP genetic ablation. Further investigation established that the accumulation of cholesteryl esters (CE, the storage form of cholesterol) rather than the content of intracellular free cholesterol, is at the center of a neuronal stress response that together triggers abnormal tau phosphorylation (via downregulation of the ubiquitin-proteasome system) and amyloid-β secretion (via APP interaction with cholesterol).

    Those results suggest that either the downregulation of Acyl-CoA cholesterol acyltransferase (ACAT, the enzyme responsible for the conversion of cholesterol in CE) or the activation of cholesterol 24S-hydroxylase (CYP46A1, which metabolizes cholesterol into 24-hydroxycholesterol and allows its export out of the cell) in neurons could be therapeutically relevant to alleviate the early events of AD neuropathology. Because CYP46A1 is only expressed in neuronal cells, it is an especially well-suited drug target, offering a unique opportunity to alleviate early AD neuropathological changes without interfering with the maintenance of cholesterol homeostasis in other cells or tissues.

    Power of the study
    The idea of modulating cholesterol metabolism to inhibit Aβ or tau neurotoxicity is not novel and has been previously explored in mouse models of amyloidosis and tauopathy, either via inhibiting ACAT activity (Hutter-Paier et al., 2004; Shibuya et al., 2015) or by overexpressing CYP46A1 in neurons (Hudry et al., 2010; Burlot et al., 2015). Nonetheless, the present study stands out for several reasons: 1) the authors identified cholesterol metabolism and CE intraneuronal accumulation as a central “druggable axis” for early signs of AD after an unbiased screen of over 1,600 compounds (a non-hypothesis driven strategy); 2) the reported effects of statins to decrease the levels of several tau phospho-epitopes were validated in familial AD- (APP duplication), sporadic AD patient- and non-demented control neurons (therefore suggesting that this approach may be impactful in all AD cases); 3) this protective impact persists in absence of APP expression (highlighting independent pathways through which CE triggers amyloid and tau pathological changes, without the necessity for a cause/consequence relationship between those neurotoxic species); 4) this study reveals how cholesterol dyshomeostasis could drive pathology in a cell-autonomous manner in human neurons, independently of the presence of astrocytes (well-known “suppliers” of cholesterol to mature neurons in the brain).

    Perspective of the study
    This work should be put in perspective with the many epidemiological studies that have tried to address the therapeutic potential of statins on dementia and AD cognitive decline (recently reviewed in  Mejias-Trueba et al., 2018; Daneschvar et al., 2015). The results of those studies have been somewhat inconsistent, and no clear consensus has been established so far. Those discrepancies could be explained by different blood-brain barrier permeabilities (able to cross or not the blood-brain barrier), the stage at which they were administered, or the distinct pharmacological effects each of those molecules can trigger throughout the body.

    In any case, the present findings by van der Kant and colleagues warrant a deeper investigation of the complex interactions between cholesterol dyshomeostasis and AD neurodegeneration, shedding new light on the significant cell-autonomous impact of CE metabolism in neurons. Whether or not Apolipoprotein E status may further modulate this phenotype is an intriguing hypothesis to explore, especially considering that the latest publication by Dr. Tsai’s lab (MIT) demonstrating dramatic differences in the transcriptional profiles of APOE4- or APOE3-iPSC-derived neurons (Lin et al., 2018).

    Finally, the authors did not comment on the other hits that had emerged from their screening effort to select Thr231-phospho-tau reducing agents (42 were initially identified, including three microtubule-interacting compounds and four statins), and one may wonder if other important molecular cascades involved in the reduction of pathological post-translational tau modifications could emerge next.

    References:

    . The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron. 2004 Oct 14;44(2):227-38. PubMed.

    . Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol Aging. 2015 Jul;36(7):2248-59. Epub 2015 Apr 7 PubMed.

    . Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther. 2010 Jan;18(1):44-53. PubMed.

    . Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology. Hum Mol Genet. 2015 Nov 1;24(21):5965-76. Epub 2015 Sep 10 PubMed.

    . Systematic review of the efficacy of statins for the treatment of Alzheimer's disease. Clin Med (Lond). 2018 Feb;18(1):54-61. PubMed.

    . Do statins prevent Alzheimer's disease? A narrative review. Eur J Intern Med. 2015 Nov;26(9):666-9. Epub 2015 Sep 2 PubMed.

    . APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.

    View all comments by Eloise Hudry
  3. We read this paper with great interest. This work provides a novel link between cholesterol esters (CE) with tau pathology in Alzheimer's disease patient-derived neurons. According to the authors, the CE effects on tau proteostasis are independent of APP and Aβ. The authors conclude that decreasing CE and/or increasing 24(S)-hydroxycholesterol is a viable strategy to reduce accumulation of pTau and Aβ in AD patients. We fully concur with this notion.

    Interestingly, the working model described in this work shows a shared pathway between cholesterol to be esterified by the esterification enzyme ACAT, and cholesterol to be converted to 24(S)-hydroxycholesterol by the enzyme Cyp46A1. In 2010, we reported that ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD, suggesting that ACAT1 and Cyp46a1 share the same cholesterol substrate pool in the AD mouse brain. We are pleased that the same concept is applicable in the AD patient iPSC derived human neuronal cells.

    Cathy Chang at the Geisel School of Medicine at Dartmouth also contributed to this comment.

    References:

    . ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3081-6. PubMed.

    View all comments by T.Y. (Ta-Yuan) Chang

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