Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes

Khatib, Thabat; Chisholm, David; Whiting, Andrew; Platt, Bettina; McCaffery, Peter

doi:10.3233/jad-190931

Cited by 20 publications

(10 citation statements)

References 122 publications

(146 reference statements)

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“…Chronic inflammation is associated with declined RA-signalling in tissues while modest decreases in endogenous RA levels are reported to enhance adipogenic differentiation [36] , [37] , [38] , [39] . Since obesity is also characterized with an increased inflammatory response, we further explored the expression of RA signals in the skeletal muscle of obese mice and the effects of RA-signalling in FAPs for muscle regeneration.…”

Section: Supplementation Of Ra Rescues Skeletal Muscle Regeneration Imentioning

confidence: 99%

Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

et al. 2020

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Background During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. Methods Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro . Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model. Findings Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice. Interpretation These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues. Funding This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D.

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Section: Supplementation Of Ra Rescues Skeletal Muscle Regeneration Imentioning

confidence: 99%

Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

et al. 2020

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“…Involvement of RA signalling in these key cognitive functions raises the questions of its role in neurodegenerative diseases. Age-related cognitive decline with impaired spatial learning and memory is associated with decreased RA signalling in elderly vertebrates (human and mice) [201,202]. In elderly mice with impaired cognitive function, the administration of 13cRA re-established RA signalling and hippocampal RARβ and RXRβ/γ expression and rescued the cognitive impairment [153,201,203].…”

Section: Contribution Of Retinoids To Chronic Neurological Disordersmentioning

confidence: 99%

“…As a specific form of dementia, Alzheimer's disease (AD) is characterized by formation of amyloid-β plaques in the CNS, which leads to inflammation and subsequent neurodegeneration [179,204]. Due to a reported decrease in RA signalling in AD patients' brains, particularly in the hippocampus region responsible for the formation of memories [201,202], retinoids, especially 13cRA, are proposed for AD treatment as neuroprotectants [123,[205][206][207][208][209]. Furthermore, specific synthetic agonists of RARα/β, such as tamibarotene, that are in use for cancer treatment, have been explored for AD treatment [209], but the clinical trials seem not to have progressed since [210].…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study

et al. 2021

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Regulatory hazard and risk assessment of endocrine-active substances currently specifies four modes of action: interference with sex hormone (oestrogen, androgen) pathways, steroidogenesis, and thyroid hormone signalling. This does not encompass the full complexity of the endocrine system and its extended interfaces with environmental pollutants that can potentially disrupt the carefully maintained balance. Here we take the retinoid signalling pathway as a European case study for both, under- and unregulated endocrine pathways and outline the different levels of interference, discuss their adversity, and indicate crosstalk to other signalling pathways. Retinoid compounds already exist in drinking water sources, occur naturally in cyanobacterial blooms and/or enter surface waters via wastewater discharge, where they pose a potential hazard to the environment and human health - a situation that can be expected to worsen due to water shortages induced by climate-change and population growth. We briefly review relevant aspects of current endocrine disruptor (ED) testing for regulatory purposes and then expand upon the needs for inclusion of disruption of retinoid signalling in (ED) regulatory safety assessment contributing to adverse health outcomes that include cognitive function and neurological disease. An overview of developmental effects of retinoid signalling disruption across species highlights critical processes and potential crosstalk with other signalling pathways. A focused weight of evidence-based evaluation of the biologically plausible associations between neurological disorders and altered retinoid signalling highlights the evidence gaps. We show that monitoring only a limited number of anthropogenic priority chemicals in water is insufficient to address the environmental risks of retinoid signalling disruption. To comprehensively assess impacts on the endpoints, processes, and pathways of the endocrine system that are most vulnerable to chemical interference we need further investigation of the true mixture composition in environmental matrices. On a weight of evidence-basis this information can then be integrated into a reliable, inclusive, quantitative approach that ultimately accommodates all the critical pathways. By focusing on the retinoid signalling pathway, we intend to improve the scope and relevance of an integrated approach for the risk assessment of endocrine disruptors.

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“…Researchers used different genetically comparable transgenic knock-in animals of AD and tau dysfunction associated with AD and dementia to investigate changes in retinoid signaling at the transcriptional levels in such models. Female rat hippocampal and frontal combined primary cultures were also used to undertake an early assessment of the therapeutic potential of a new family of synthetic retinoids (RAR-M1) that target both biological and non-biological receptors ( Endres et al, 2014a ; Khatib et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) is perceived with various pathophysiological characteristics such oxidative stress, senile plaques, neuroinflammation, altered neurotransmission immunological changes, neurodegenerative pathways, and age-linked alterations. A great deal of studies even now are carried out for comprehensive understanding of pathological processes of AD, though many agents are in clinical trials for the treatment of AD. Retinoids and retinoic acid receptors (RARs) are pertinent to such attributes of the disease. Retinoids support the proper functioning of the immunological pathways, and are very potent immunomodulators. The nervous system relies heavily on retinoic acid signaling. The disruption of retinoid signaling relates to several pathogenic mechanisms in the normal brain. Retinoids play critical functions in the neuronal organization, differentiation, and axonal growth in the normal functioning of the brain. Disturbed retinoic acid signaling causes inflammatory responses, mitochondrial impairment, oxidative stress, and neurodegeneration, leading to Alzheimer’s disease (AD) progression. Retinoids interfere with the production and release of neuroinflammatory chemokines and cytokines which are located to be activated in the pathogenesis of AD. Also, stimulating nuclear retinoid receptors reduces amyloid aggregation, lowers neurodegeneration, and thus restricts Alzheimer’s disease progression in preclinical studies. We outlined the physiology of retinoids in this review, focusing on their possible neuroprotective actions, which will aid in elucidating the critical function of such receptors in AD pathogenesis.

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Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes

Cited by 20 publications

References 122 publications

Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study

Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease

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