Litvinchuk A, Suh JH, Guo JL, Lin K, Davis SS, Bien-Ly N, Tycksen E, Tabor GT, Remolina Serrano J, Manis M, Bao X, Lee C, Bosch M, Perez EJ, Yuede CM, Cashikar AG, Ulrich JD, Di Paolo G, Holtzman DM. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron. 2024 Feb 7;112(3):384-403.e8. Epub 2023 Nov 22 PubMed. Neuron

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  1. The 2017 Nature paper by the Holtzman group describing their findings that ApoE accelerates Tau pathology (Shi et al., 2017), even in the absence of amyloid pathology (van der Kant et al., 2020), has been a major conceptual breakthrough in understanding the role of ApoE in Alzheimer’s pathology. With impressive follow-up through a number of papers, the Holtzman lab and others have probed which cell types are involved, and which other factors—e.g., diet, sleep—might modify the ApoE4 effect on Tau.

    I’m excited by this new study because it dives deeper into the mechanisms of how ApoE4 might affect Tau. A very plausible candidate for these effects is altered lipid/cholesterol metabolism. ApoE4 is the main brain cholesterol carrier, and is known to disrupt cholesterol metabolism in different model systems and cell types (Blanchard et al., 2022; TCW et al., 2019). Furthermore, we showed that cholesterol accumulation in neurons drives Tau accumulation (van der Kant et al., 2019), while more recently Tau mutations have been shown to regulate cholesterol homeostasis (Glasauer et al., 2022; Szabo et al., 2023). 

    Interestingly, the authors report here for the first time that cholesterol metabolism is indeed significantly altered in P301S/ApoE4 transgenic mice. Through a series of well-crafted lipidomic experiments, they show changes in cholesterol, its storage products, but also changes in lysosomal lipids. More importantly, they show rescue of many of these phenotypes by an LXR agonist and ABCA1 overexpression, both known to drive cholesterol export. The authors go on to show that the LXR agonist can partially rescue Tau pathology and inflammation in these mice, as well as improve behavioral deficits.

    This paper provides an important proof of concept for the role cholesterol has in mediating the effects of ApoE4 on Tau pathology. This effect might be driven through glial lipid changes and downstream inflammatory processes, as recent work has uncovered the importance of lipids in glial activation. The authors also report less phosphorylated Tau in the neurons (and more proteasome), which could also indicate neuronal cholesterol-dependent effects on the proteasome and pTau degradation, as we have shown in iPSC-neurons (van der Kant et al., 2019). 

    LXR agonists have been clinically explored for the treatment of atherosclerosis, but have not reached the market due to severe off-target effects on fatty acid metabolism, i.e., fatty liver phenotypes. Indeed, the authors also see increased fatty acid accumulation in the brains of the LXR-treated P301S/ApoE4 mice. This paper therefore solidifies the link between ApoE, cholesterol homeostasis and Tau, but also highlights the need for more specific brain-cholesterol targeting interventions. This paper will likely serve as a blueprint for future work aimed to mitigate ApoE4- and Tau-mediated (lipid) dysfunction by candidate interventions 

    References:

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    van der Kant R, Goldstein LS, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020 Jan;21(1):21-35. Epub 2019 Nov 28 PubMed.

    Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R'Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022 Nov;611(7937):769-779. Epub 2022 Nov 16 PubMed.

    TCW J, Liang SA, Qian L, Pipalia NH, Chao MJ, Shi Y, Bertelsen SE, Kapoor M, Marcora E, Sikora E, Holtzman DM, Maxfield FR, Zhang B, Wang M, Poon WW, Goate AM. Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. 2019 Jul 25 10.1101/713362 (version 1) bioRxiv.

    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 LS. 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.

    Glasauer SM, Goderie SK, Rauch JN, Guzman E, Audouard M, Bertucci T, Joy S, Rommelfanger E, Luna G, Keane-Rivera E, Lotz S, Borden S, Armando AM, Quehenberger O, Temple S, Kosik KS. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Reports. 2022 Sep 13;17(9):2127-2140. Epub 2022 Aug 18 PubMed.

    Szabo L, Cummins N, Paganetti P, Odermatt A, Papassotiropoulos A, Karch C, Götz J, Eckert A, Grimm A. ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein. EMBO Rep. 2023 Aug 3;24(8):e57499. Epub 2023 Jul 4 PubMed.

    View all comments by Rik van der Kant

  2. In this paper, the Holtzman group continues to systematically dissect ApoE4 involvement in tau-mediated neurodegeneration and inflammation. This set of experiments highlights the critical role of lipid metabolism in the progression of pathology and builds on other recent work showing that a toxic accumulation of microglial cholesterol esters is a central feature of the lipid mechanism.

    An important missing link in the mechanism is what’s happening in neurons and when. There is no final consensus on LXR expression in adult neurons, but considering neuronal cell-cycle re-entry in AD, what would be the direct LXR agonist effect on neuronal cells? Work from our lab shows a significant reduction in cholesterol esters in surviving synapses from the human AD cortex (Bilousova et al., 2019) and earlier work showed accumulations of both free cholesterol and ganglioside GM1 in synapses positive for Aβ (Gylys et al., 2007). These synaptic changes seem likely to be downstream from lipid changes in microglia and astrocytes and may not be related. But these changes in synapses, which are enveloped by astrocytic and microglial processes, illustrate the complexity of understanding APOE-mediated lipid changes in disease progression.

    The Litvinchuk paper also points to the potential of LXR agonists as disease-modifying therapies and the urgent need for next-generation LXR agonists without the peripheral effects of GW3965 and T0901317 on cholesterol metabolism, triglycerides, and insulin secretion by pancreatic beta-cells (Maczewsky et al., 2020).

    —Tina Bilousova, University of California, San Francisco, is the co-author of this comment.

    References:

    Bilousova T, Melnik M, Miyoshi E, Gonzalez BL, Poon WW, Vinters HV, Miller CA, Corrada MM, Kawas C, Hatami A, Albay R 3rd, Glabe C, Gylys KH. Apolipoprotein E/Amyloid-β Complex Accumulates in Alzheimer Disease Cortical Synapses via Apolipoprotein E Receptors and Is Enhanced by APOE4. Am J Pathol. 2019 Aug;189(8):1621-1636. Epub 2019 May 17 PubMed.

    Gylys KH, Fein JA, Yang F, Miller CA, Cole GM. Increased cholesterol in Abeta-positive nerve terminals from Alzheimer's disease cortex. Neurobiol Aging. 2007 Jan;28(1):8-17. PubMed.

    Maczewsky J, Kaiser J, Krippeit-Drews P, Drews G. Approved LXR agonists exert unspecific effects on pancreatic β-cell function. Endocrine. 2020 Jun;68(3):526-535. Epub 2020 Mar 7 PubMed.

    View all comments by Karen Gylys

  3. This article presents the therapeutic effects of the LXR ligand GW3965 in 9.5-month-old tau transgenic mice expressing human E3 (TE3) or E4 (TE4) as well as their E3 and E4 non-transgenic controls. The authors evaluated several parameters indicative of neurodegeneration: 1) nest-building behavior (generalized as behavioral deficit); 2) p-tau levels, without affecting APOE levels; 3) glial reactivity, T cell infiltration, and inflammation, and 4) synaptic loss. They also report that the application of GW3965 changed the transcriptional response in TE4 mice. Additionally, they performed lipidomics on forebrain tissue and on isolated microglia and astrocytes. In forebrain, they found that several species of cholesteryl esters were increased in TE4 versus TE3 mice. Interestingly, the same species were decreased in E4 versus E3 mice, suggesting that tau pathology may contribute to this effect. In contrast, cholesterol sulfate, and several phospholipids and diacylglyceride species, were decreased in TE4 versus TE3 mice.

    Then, based on what the authors found after application of a pharmacologically active synthetic ligand of nuclear receptors LXR/RXR, they conclude that “promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.”

    There have been dozens of studies demonstrating that promoting the efflux of major brain cells' lipids should be considered a rational and physiologically justifiable therapeutic approach in Alzheimer's disease. The mere fact that a synthetic LXR ligand, as the authors have demonstrated, may have a therapeutic effect in a model of tauopathy is a significant contribution to the understanding of the role of LXR-responsive genes in neurodegeneration, and reopens the door for exploring therapeutic strategies proposed years ago.

    The list of remarkable responses to an experimental therapeutic agent in a mouse model of tauopathy is probably unique among many disorders, not only neurodegenerative ones. In a complex mouse model expressing mutant tau and human APOE4, a reasonable explanation of the plethora of ligand-activated LXR/RXR effects is through the LXR/RXR-ABCA1-APOE regulatory axis. While the methods used here did not reveal upregulation of APOE—neither at genomic nor at protein level—clearly a significant part of the effects of the synthetic ligand is mediated by ABCA1 upregulation.

    Importantly, the effects of GW3965 mimic the phenotype of ABCA1 transgenic mice. Considering the limited, but extremely important functions of ABCA1 in brain, the results of this study will doubtlessly stimulate a new wave of research on the decades-old and valid hypothesis that major aspects of brain lipid metabolism depend on the LXR/RXR-ABCA1 regulatory axis with significant impact on neurodegeneration.

    View all comments by Iliya Lefterov

  4. There is a complex relationship between lipid metabolism and AD pathophysiology. ApoE is a major genetic risk factor for late-onset AD and the major lipid carrier in the central nervous system. In the brain, apoE also mediates the removal of cholesterol in a process known as cholesterol efflux. This is particularly important for phagocytic cells such as microglia that ingest vast amounts of lipids, and impaired or saturated cholesterol efflux can trigger other cellular responses including altered lysosomal function and transcriptomic profiles. On the other hand, augmenting cholesterol efflux capacity, which can be accomplished by genetic or pharmacological means, is generally considered beneficial.

    The best-studied class of molecules that promote expression of genes involved in cholesterol efflux are agonists of the liver X receptor (LXR), which stimulate expression genes such as ABC transporter cassette A1 (ABCA1) and apolipoprotein cholesterol acceptors such as apoE and apoA1 (Hua and Wei, 2023). Previous studies evaluating LXR agonists in AD animal models focused mainly on amyloid pathways (Donkin et al., 2010; Fitz et al., 2014; Lefterov et al., 2007; Terwel et al., 2011). 

    Here, Alexandra Litvinchuk from David Holtzman’s laboratory investigated the effect of the LXR agonist GW3965 as well as overexpression of ABCA1 on tau and apoE4-linked glial lipid accumulation and neurodegeneration. Using targeted lipidomics, they found that 9.5-month-old P301S tau mice expressing human apoE4 had elevated cholesterol esters in the forebrain, increased lipid accumulation in microglia, and altered cholesterol metabolism in microglia and astrocytes. Initiation of oral GW3965 treatment at 6 months of age attenuated neurodegeneration, improved nesting behavior, and reduced tauopathy as measured by AT8 and ptau immunostaining. As expected from previous reports, there was no change in brain apoE levels, suggesting that changes in apoE lipidation status rather than apoE expression were driving the effects observed.

    Intriguingly, GW3965 treatment also reduced T-cell infiltration and inflammation. This observation is of key importance as peripheral lipoprotein-mediated signaling may be involved in regulating T-cell infiltration to the CNS and systemic administration of GW3965 would also affect peripheral pathways. Litvinchuk also found that selective overexpression of ABCA1 in the brain also reduced neurodegeneration, tauopathy, microglial activation, and lipid accumulation in tau-apoE mice, suggesting that enhancing cholesterol efflux selectively in the brain is sufficient to drive many of the beneficial effects observed. However, T-cell infiltration was not reported for this experiment. It will be interesting to further explore this component, as peripheral lipoprotein subclasses have complex relationships with inflammatory and immunomodulatory pathways including Tregs (Pinzon Grimaldos et al., 2022) and oral GW3965 administration would affect peripheral cholesterol efflux but brain-specific ABCA1 overexpression would not.

    One challenge for future translation into clinical utility is that small-molecule LXR agonists have several adverse effects in humans, including stimulation of hepatic lipogenesis that increased pro-atherogenic low-density-lipoprotein levels. One potential solution could be administration directly to the CNS to limit systemic exposure. Another solution could involve capitalizing on the synergy between circulating high density lipoproteins and LXR agonism (Morin et al., 2020), if further research supports a role for peripheral lipoproteins on immune cell access to the CNS and tau-mediated neurodegeneration. 

    View all comments by Cheryl Wellington

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News

  1. Do APOE4’s Lipid Shenanigans Trigger Tauopathy?

Mutations

  1. MAPT P301S