LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer’s disease

Sandoval-Hernández, Adrián G.; Restrepo, Alejandro; Cardona‐Gómez, Gloria Patricia; Arboleda, Gonzálo

doi:10.1016/j.neulet.2016.04.007

Cited by 22 publications

(15 citation statements)

References 32 publications

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“…Age-related neurodegenerative conditions have been linked to the disruption of cholesterol metabolism and LXR signaling (118). Likewise, LXR agonists have been shown to produce cognitive improvement in AD mouse models (121)(122)(123), but the mechanisms are not well understood. It has been suggested that the protective effects of LXR agonists are achieved by promotion of an increase in phagocytosis of amyloid-β by microglia (117), by inhibition of microglia nitric oxide synthetase (NOS) activity (124), or by attenuation of the microglia inflammatory response (125).…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Transcriptional control of microglia phenotypes in health and disease

Holtman¹,

Skola²,

Glass³

2017

Journal of Clinical Investigation

175

156

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Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Transcriptional control of microglia phenotypes in health and disease

Holtman¹,

Skola²,

Glass³

2017

Journal of Clinical Investigation

175

156

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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 LXR agonist also exhibited significant beneficial effects on the disruption of the brain neurovascular unit in a mouse AD model. In very old (24 months) 3xTg‐AD mice, short‐term GW3965 treatment was able to significantly decrease astrogliosis and partially restore the hippocampal microvascular morphology by decreasing tortuosity and increasing its length (Sandoval‐Hernandez, Restrepo, Cardona‐Gomez, & Arboleda, ). This restoration in the microvasculature could have a significant impact on neuronal function and hippocampal‐dependent learning and memory, which is greatly impacted by AD pathology.…”

Section: Liver X Receptorsmentioning

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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LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer’s disease

Cited by 22 publications

References 32 publications

Transcriptional control of microglia phenotypes in health and disease

Transcriptional control of microglia phenotypes in health and disease

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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