β-Carotene, a Potent Amyloid Aggregation Inhibitor, Promotes Disordered Aβ Fibrillar Structure

Banerjee, Siddhartha; Baghel, Divya; Oliveira, Ana Pacheco de; Ghosh, Ayanjeet

doi:10.3390/ijms24065175

Cited by 5 publications

(2 citation statements)

References 40 publications

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“…Consistent with this view, previous reports that have identified carotenoids in plaques have argued that plaques are seen as a type of inflammation by the immune system and that carotenoids accumulate in the plaques to try to stop mitigate the inflammation process. − Other studies have suggested that carotenoids can be used in the treatment of AD, reducing cognitive impairment. − It is known that β-carotene can inhibit Aβ aggregation, but detailed molecular mechanisms of inhibition are not known. Recent studies by Banerjee et al have shown that β-carotene promotes structural disorder in fibrils but does not necessarily prevent fibril formation. These would lead to expectations that carotenoids should be associated with plaques exhibiting lesser β-sheet character.…”

Section: Resultsmentioning

confidence: 99%

Colocalization of β-Sheets and Carotenoids in Aβ Plaques Revealed with Multimodal Spatially Resolved Vibrational Spectroscopy

de Oliveira,

Chase,

Confer

et al. 2023

J. Phys. Chem. B

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The aggregation of amyloid β(Aβ) peptides is at the heart of Alzheimer's disease development and progression. As a result, amyloid aggregates have been studied extensively in vitro, and detailed structural information on fibrillar amyloid aggregates is available. However, forwarding these structural models to amyloid plaques in the human brain is still a major challenge. The chemistry of amyloid plaques, particularly in terms of the protein secondary structure and associated chemical moieties, remains poorly understood. In this report, we use Raman microspectroscopy to identify the presence of carotenoids in amyloid plaques and demonstrate that the abundance of carotenoids is correlated with the overall protein secondary structure of plaques, specifically to the population of β-sheets. While the association of carotenoids with plaques has been previously identified, their correlation with the β structure has never been identified. To further validate these findings, we have used optical photothermal infrared (O-PTIR) spectroscopy, which is a spatially resolved technique that yields complementary infrared contrast to Raman. O-PTIR unequivocally demonstrates the presence of elevated β-sheets in carotenoidcontaining plaques and the lack of β structure in noncarotenoid plaques. Our findings underscore the potential link between antiinflammatory species as carotenoids to specific secondary structural motifs within Aβ plaques and highlight the possible role of chemically distinct plaques in neuroinflammation, which can uncover new mechanistic insights and lead to new therapeutic strategies for AD.

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Section: Resultsmentioning

confidence: 99%

Colocalization of β-Sheets and Carotenoids in Aβ Plaques Revealed with Multimodal Spatially Resolved Vibrational Spectroscopy

de Oliveira,

Chase,

Confer

et al. 2023

J. Phys. Chem. B

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“…In a subsequent investigation, the precise mechanism by which β-carotene regulates Aβ aggregation was unveiled, which does not relate to the direct inhibition of Aβ fibrillation or alteration of the morphology of Aβ 42 aggregates. Instead, they discovered that β-carotene modulates Aβ aggregation by promoting fibrillar polymorphs devoid of the structural order required for the formation of fibrillar aggregates [ 97 ]. β-carotene has also been identified as an effective competitive inhibitor for AChE with a binding mode similar to that of rivastigmine and galantamine, suggesting that it may be employed as a natural pharmaceutical for the management of AD [ 98 ].…”

Section: Neuroprotective Effects Of Macroalgae- and Microalgae-derive...mentioning

confidence: 99%

Natural Bioactive Compounds from Macroalgae and Microalgae for the Treatment of Alzheimer’s Disease: A Review

Lee,

Wong,

Koh

et al. 2024

Yale J Biol Med

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Exploration of phytoconstituents of Medhya Rasayana herbs to identify potential inhibitors for cerebroside sulfotransferase through high-throughput screening

Singh,

Singh

2024

Front. Mol. Biosci.

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Cerebroside sulfotransferase (CST) is a key enzyme in sulfatide biosynthesis and regulation of the myelin sheath in the nervous system. To counter sulfatide accumulation with the deficiency of aryl sulfatase A, CST is considered a target protein in substrate reduction therapy in metachromatic leukodystrophy. In this study, 461 phytoconstituents from four herbs of Medhya Rasayana were screened using multi-pronged virtual screening methods including molecular docking, molecular dynamics (MD) simulation, and reverse pharmacophore analysis. The initial screening of the top 15 hits was based on the binding affinity of the compounds toward the CST substrate-binding site using the lowest free energy of a binding score cutoff of ≤ −7.5 kcal/mol, with the number of conformations in the largest cluster more than 75. The absorption, distribution, metabolism, and excretion (ADME) and toxicity-based pharmacokinetic analysis delivered the top four hits: 18alpha-glycyrrhetinic acid, lupeol, alpha carotene, and beta-carotene, with high blood–brain barrier permeability and negligible toxicity. Furthermore, a 100-ns simulation of protein–ligand complexes with a trajectory analysis of structural deviation, compactness, intramolecular interactions, principal component analysis, free energy landscape, and dynamic cross-correlation analysis showed the binding potential and positioning of the four hits in the binding pocket. Thus, an in-depth analysis of protein–ligand interactions from pre- and post-molecular dynamics simulation, along with reverse pharmacophore mapping, suggests that 18alpha-glycyrrhetinic acid is the most potent and specific CST inhibitor, while beta-carotene could be considered the second most potent compound for CST inhibition as it also exhibited overall stability throughout the simulation. Therefore, the computational drug screening approach applied in this study may contribute to the development of oral drugs as a therapeutic option for metachromatic leukodystrophy.

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β-Carotene, a Potent Amyloid Aggregation Inhibitor, Promotes Disordered Aβ Fibrillar Structure

Cited by 5 publications

References 40 publications

Colocalization of β-Sheets and Carotenoids in Aβ Plaques Revealed with Multimodal Spatially Resolved Vibrational Spectroscopy

Colocalization of β-Sheets and Carotenoids in Aβ Plaques Revealed with Multimodal Spatially Resolved Vibrational Spectroscopy

Natural Bioactive Compounds from Macroalgae and Microalgae for the Treatment of Alzheimer’s Disease: A Review

Exploration of phytoconstituents of Medhya Rasayana herbs to identify potential inhibitors for cerebroside sulfotransferase through high-throughput screening

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