Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

Stachel, Shawn J.; Zerbinatti, Celina; Rudd, Michael T.; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K.; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M.; Michener, Maria S.; Szczerba, Peter; Brnardic, Edward J.; Rada, Vanessa; Kim, Yun-Tae; Meißner, Robert; Wuelfing, Peter; Yuan, Yuan; Ballard, Jeanine; Holahan, Marie A.; Klein, Daniel; Jun, Lu; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N.; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew; Bennett, David Jonathan; Bilodeau, Mark T.; Renger, John J.

doi:10.1021/acs.jmedchem.6b00176

Cited by 40 publications

(45 citation statements)

References 27 publications

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“…Accumulating evidence suggests a role for a disturbed cholesterol turnover in the central nervous system (CNS) in AD pathogenesis [2][3][4][5][6][7][8][9][10][11] . In line with this, stimulation of cholesterol turnover improves disease outcome in animal models of AD 2,[12][13][14][15][16][17][18] . Liver X receptors (LXR) are master regulators of cholesterol and triglyceride turnover and suppress an inflammatory transcriptional profile via trans-repression of NFκB signaling 19 .…”

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confidence: 60%

Dietary Sargassum Fusiforme Improves Memory And Reduces Amyloid Plaque Load In An Alzheimer’s Disease Mouse Model

et al. 2019

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Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXRβ. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal Aβ plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRα activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of Aβ 42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of Aβ. our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXRβ activation.

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confidence: 60%

Dietary Sargassum Fusiforme Improves Memory And Reduces Amyloid Plaque Load In An Alzheimer’s Disease Mouse Model

et al. 2019

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“…The two isoforms of the transcription factor liver X receptor (LXR-α and LXR-β) are activated and hence translocated to the nucleus by the oxidized derivatives of cholesterol (oxysterols), which are formed by the high redox stress produced by malfunctioning mitochondria are also highlighted in the scheme neurodegeneration (Bond et al, 2018;Sandoval-Hernandez, Restrepo, Cardona-Gomez, & Arboleda, 2016;Stachel et al, 2016). The Figure shows the major mechanisms of cholesterol influx (e.g., TSPO) into the mitochondria, exploited by the intracellular accumulation of APOE.…”

Section: Discussionmentioning

confidence: 99%

“…The Figure shows the major mechanisms of cholesterol influx (e.g., TSPO) into the mitochondria, exploited by the intracellular accumulation of APOE. The two isoforms of the transcription factor liver X receptor (LXR-α and LXR-β) are activated and hence translocated to the nucleus by the oxidized derivatives of cholesterol (oxysterols), which are formed by the high redox stress produced by malfunctioning mitochondria are also highlighted in the scheme neurodegeneration (Bond et al, 2018;Sandoval-Hernandez, Restrepo, Cardona-Gomez, & Arboleda, 2016;Stachel et al, 2016). Along with the need to continue gathering evidence on the beneficial effect of cholesterol-modulating agents on neurodegeneration, it is crucial to devise novel means of measuring neuroprotection, such as the handling of lipids by mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai

Campanella

2019

British J Pharmacology

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The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…An example of this potential is a recently developed LXRβ selective agonist, which increased levels of ABCA1 and soluble APOE with diminished levels of soluble Aβ. Mice treated with this LXRβ selective agonist failed to exhibit the increased liver fat content observed with nonselective LXR agonist (Stachel et al, ).…”

Section: Future Directionsmentioning

confidence: 99%

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease

Fitz

Nam

Koldamova

et al. 2019

British J Pharmacology

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After 15 years of research into Alzheimer's disease (AD) therapeutics, including billions of US dollars provided by federal agencies, pharmaceutical companies, and private foundations, there are still no meaningful therapies that can delay the onset or slow the progression of AD. An understanding of the proteolytic processing of amyloid precursor protein (APP) and the hypothesis that pathogenic mechanisms in familial and sporadic forms of AD are very similar led to the assumption that pharmacological inhibition of secretases or immunological approaches to clear amyloid depositions in the brain would have been the core to drug discovery strategies and successful therapies. However, there are other understudied approaches including targeting genes, gene networks, and metabolic pathways outside the proteolytic processing of APP. The advancement of newly developed sequencing technologies and mass spectrometry, as well as the availability of animal models expressing human apolipoprotein E isoforms, has been critical in rationalizing additional AD therapeutics. The purpose of this review is to present one of those approaches, based on the role of ligand‐activated nuclear liver X and retinoid X receptors in the brain. This therapeutic approach was initially proposed utilizing in vitro models 15 years ago and has since been examined in numerous studies using AD‐like mouse models. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

Cited by 40 publications

References 27 publications

Dietary Sargassum Fusiforme Improves Memory And Reduces Amyloid Plaque Load In An Alzheimer’s Disease Mouse Model

Dietary Sargassum Fusiforme Improves Memory And Reduces Amyloid Plaque Load In An Alzheimer’s Disease Mouse Model

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease

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