Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells

Fanaee-Danesh, Elham; Gali, Chaitanya Chakravarthi; Tadić, Jelena; Zandl-Lang, Martina; Kober, Alexandra; Roca-Agujetas, Vicente; Dios, Cristina de; Tam‐Amersdorfer, Carmen; Stracke, Anika; Albrecher, Nicole Maria; Manavalan, Anil Paul Chirackal; Reiter, Marielies; Sun, Yidan; Colell, Anna; Madeo, Frank; Malle, Ernst; Panzenboeck, Ute

doi:10.1016/j.bbadis.2019.04.019

Cited by 35 publications

(35 citation statements)

References 106 publications

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“…The present results indicated that astaxanthin decreased Ab42 deposition and prevented memory decline in the App NL-G-F mice. Consistently, two recent studies reported that astaxanthin reduced Ab40 levels in a 3xTg AD mouse model (Fanaee-Danesh et al, 2019) and reduced Ab42 levels in rats with intracerebroventricular injections of Ab42 (Rahman et al, 2019). The present study further indicated that astaxanthin decreased pTau and the Iba1 fraction, while it increased hippocampal PV-positive neuron density and total GSH levels.…”

Section: Protective Mechanisms Of Astaxanthinsupporting

confidence: 91%

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

et al. 2020

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Growing evidence suggests that oxidative stress due to amyloid b (Ab) accumulation is involved in Alzheimer's disease (AD) through the formation of amyloid plaque, which leads to hyperphosphorylation of tau, microglial activation, and cognitive deficits. The dysfunction or phenotypic loss of parvalbumin (PV)-positive neurons has been implicated in cognitive deficits. Astaxanthin is one of carotenoids and known as a highly potent antioxidant. We hypothesized that astaxanthin's antioxidant effects may prevent the onset of cognitive deficits in AD by preventing AD pathological processes associated with oxidative stress. In the present study, we investigated the effects of astaxanthin intake on the cognitive and pathological progression of AD in a mouse model of AD. The App NL-G-F/NL-G-F mice were fed with or without astaxanthin from 5-to-6 weeks old, and cognitive functions were evaluated using a Barnes maze test at 6 months old. PV-positive neurons were investigated in the hippocampus. Ab42 deposits, accumulation of microglia, and phosphorylated tau (pTau) were immunohistochemically analyzed in the hippocampus. The hippocampal anti-oxidant status was also investigated. The Barnes maze test indicated that astaxanthin significantly ameliorated memory deficits. Astaxanthin reduced Ab42 deposition and pTau-positive areal fraction, while it increased PVpositive neuron density and microglial accumulation per unit fraction of Ab42 deposition in the hippocampus. Furthermore, astaxanthin increased total glutathione (GSH) levels, although 4-hydroxy-2,3-trans-nonenal (4-HNE) protein adduct levels (oxidative stress marker) remained high in the astaxanthin supplemented mice. The results indicated that astaxanthin ameliorated memory deficits and significantly reversed AD pathological processes (Ab42 deposition, pTau formation, GSH decrease, and PV-positive neuronal

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Section: Protective Mechanisms Of Astaxanthinsupporting

confidence: 91%

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

et al. 2020

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“…At 10 nM, AST was found to double the mRNA expression of ADAM10 in primary porcine brain capillary endothelial cells [132]. Moreover, AST, presumably via PPARα agonism, also increased endothelial expression of lipoprotein receptor-related protein 1 (LRP1), a protein expressed on the abluminal surface of brain capillaries that functions to transport amyloid β monomers and oligomers from the brain [132,133]. Importantly, genetic knockout of LRP1 in 5XFAD AD model mice elevates their brain levels of soluble amyloid β and exacerbates their cognitive dysfunction [133].…”

Section: Controlling Amyloid β Production Via Modulation Of Bace1 and Adam10 Expressionmentioning

confidence: 95%

“…Remarkably, AST can act as a PPARα agonist in physiologically relevant low nanomolar concentrations [130,131]. At 10 nM, AST was found to double the mRNA expression of ADAM10 in primary porcine brain capillary endothelial cells [132]. Moreover, AST, presumably via PPARα agonism, also increased endothelial expression of lipoprotein receptor-related protein 1 (LRP1), a protein expressed on the abluminal surface of brain capillaries that functions to transport amyloid β monomers and oligomers from the brain [132,133].…”

Section: Controlling Amyloid β Production Via Modulation Of Bace1 and Adam10 Expressionmentioning

confidence: 99%

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

McCarty

DiNicolantonio

Lerner

2021

IJMS

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Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer’s disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid β oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid β monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1β, which potentiates the neurotoxicity of amyloid β. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.

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“…Similarly, the effect of the peroxisome proliferator‐activated receptor α agonist, astaxanthin on cellular cholesterol metabolism, APP processing/production has been demonstrated with the help of 3xTg AD mice. This study revealed that astaxanthin can reduce BACE1 and increase LRP‐1 expression in 3xTgAD mice brain (Fanaee‐Danesh et al., 2019).…”

Section: Introduction To Oxysterolsmentioning

confidence: 89%

Novel therapeutic strategies for Alzheimer’s disease targeting brain cholesterol homeostasis

Samant

Gupta

2020

Eur J of Neuroscience

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Aβ plaques and tauopathy are two major concerns associated with AD. Moreover, excessive Aβ accumulation can lead to other nonspecific metabolic brain abnormalities. There are various genetic, environmental, and other risk factors associated with AD. Identification of risk factors and its mechanisms by which these factors impart role in AD pathology would be helpful for the prevention of AD progression. Altered cholesterol homeostasis could be considered as a risk factor for AD progression. Brain cholesterol dysmetabolism is recognized as one of the crucial attributes for AD that affect major hallmarks of AD including neurodegeneration. To fill the gap between altered cholesterol levels in the brain and AD, the researchers started focusing on statins as re‐purposing drugs for AD treatment. The various other hypothesis has been suggested due to a lack of beneficial results of statins in clinical trials, such as reduced brain cholesterol could underlie poor cognition. Unfortunately, it is still unclear, whether an increase or decrease in brain cholesterol levels responsible for Alzheimer's disease or not. Presently, scientists believed that managing the level of cholesterol in the brain may help as an alternative treatment strategy for AD. In this review, we focused on the therapeutic strategies for AD by targeting brain cholesterol levels.

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Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells

Cited by 35 publications

References 106 publications

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

Novel therapeutic strategies for Alzheimer’s disease targeting brain cholesterol homeostasis

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