Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP

Atali, Sarah; Dorandish, Sadaf; Devos, Jonathan; Williams, Asana; Price, Deanna; Taylor, Jaylen; Guthrie, Jeffrey; Heyl, Deborah L.; Evans, Hedeel Guy

doi:10.1002/2211-5463.13023

Cited by 17 publications

(26 citation statements)

References 107 publications

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“…Earlier, we showed that immunodepletion of the neuroprotective peptide, humanin, from the media of A549 and H1299 cells increased the relative abundance of oligomer vs. total levels of amyloid beta, a peptide involved in the Alzheimer disease process, and was correlated with diminished cell viability and increased apoptosis [56]. We then found that ATP, thought to reduce misfolding of amyloid beta, strengthened interactions between amyloid beta and humanin [57]. More recently, we showed that higher intact amyloid beta 40/42 levels are present in the media of A549 (p53 wild-type) than in H1299 (p53-null) lung cancer cell media [44].…”

Section: Discussionmentioning

confidence: 86%

Differences in the Relative Abundance of ProBDNF and Mature BDNF in A549 and H1299 Human Lung Cancer Cell Media

Dorandish

Atali

Ray

et al. 2021

IJMS

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Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to several human malignancies and shown to promote tumorigenesis. The purpose of this study was to explore the relative abundance of pro-brain-derived neurotrophic factor (proBDNF) and mature BDNF (mBDNF) in A549 (p53 wild-type) and H1299 (p53-null) lung cancer cell media. Higher levels of proBDNF were detected in the media of A549 cells than in H1299 cell media. Using inhibitors, we found that the levels of proBDNF and mBDNF in the media are likely regulated by PI3K, AKT, and NFκB. However, the largest change in these levels resulted from MMP2/9 inhibition. Blocking p53 function in A549 cells resulted in increased mBDNF and decreased proBDNF, suggesting a role for p53 in regulating these levels. The ratio of proBDNF/mBDNF was not affected by MMP2 knockdown but increased in the media of both cell lines upon knockdown of MMP9. Downregulation of either MMP2 or MMP9 by siRNA showed that MMP9 siRNA treatment of either A549 or H1299 cells resulted in decreased cell viability and increased apoptosis, an effect diminished upon the same treatment with proBDNF immunodepleted media, suggesting that MMP9 regulates the cytotoxic effects induced by proBDNF in lung cancer cells.

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Section: Discussionmentioning

confidence: 86%

Differences in the Relative Abundance of ProBDNF and Mature BDNF in A549 and H1299 Human Lung Cancer Cell Media

Dorandish

Atali

Ray

et al. 2021

IJMS

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“…We also found that the relative abundance of Aβ oligomer versus total Aβ increased upon immunodepletion of the cytoprotective peptide, humanin, from the conditioned media of A549 and H1299 cells, leading to increased apoptosis and diminished cell viability 52 . More recently, we showed that ATP, thought to decrease misfolding of Aβ, strengthened interactions between humanin and Aβ but weakened those between Aβ and acetylcholinesterase 53 . More humanin was bound to Aβ upon ATP addition to media from either A549 or H1299 lung cancer cells, while reduced acetylcholinesterase levels were found in a complex with Aβ by ATP addition to A549 cell media 53 .…”

Section: Resultsmentioning

confidence: 95%

“…More recently, we showed that ATP, thought to decrease misfolding of Aβ, strengthened interactions between humanin and Aβ but weakened those between Aβ and acetylcholinesterase 53 . More humanin was bound to Aβ upon ATP addition to media from either A549 or H1299 lung cancer cells, while reduced acetylcholinesterase levels were found in a complex with Aβ by ATP addition to A549 cell media 53 . To better understand the mechanisms regulating the levels of Aβ in the media, A549 and H1299 cells were grown in FBS-supplemented media for 24 h, then incubated in serum-free media overnight.…”

Section: Resultsmentioning

confidence: 95%

“…Conditioned media was immunodepleted (ID) according to methods previously described 118 and our recently published reports 53 , 57 . ID media was prepared by first growing cells in FBS-supplemented media for 24 h. The cells were then incubated in serum-free media overnight then with the indicated treatments for 72 h. The media was next collected and depleted sequentially from Aβ using first 6E10 antibodies (“ Methods ” section).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of amyloid-β levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells

Dorandish

Williams

Atali

et al. 2021

Sci Rep

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In this study, we set out to identify regulators of intact amyloid-β40/42 (Aβ) levels in A549 (p53 wild-type) and H1299 (p53-null) lung cancer cell media. Higher Aβ levels were detected in the media of A549 than H1299 cells without or with treatment with 4-methylumbelliferone (4-MU) and/or the anti-CD44 antibody (5F12). Using inhibitors, we found that PI3K, AKT, and NFκB are likely involved in regulating Aβ levels in the media. However, increased Aβ levels that more closely resembled those found upon 4-MU co-treatment resulted from MMP2/9 inhibition, suggesting that MMP2/9 maybe the main contributors to regulation of Aβ levels in the media. Differences in Aβ levels might be accounted for, in part, by p53 since blocking p53 function in A549 cells resulted in decreased Aβ levels, increased MMP2/9 levels, increased PI3K/AKT activities and the phospho/total NFκB ratio. Using siRNA targeted against MMP2 or MMP9, we found increased Aβ levels in the media, however, MMP2 knockdown led to Aβ levels closely mimicking those detected by co-treatment with 4-MU. Cell viability or apoptosis upon treatment with either MMP2 or MMP9 siRNA along with Aβ immunodepletion, showed that MMP2 is the predominant regulator of the cytotoxic effects induced by Aβ in lung cancer cells.

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“…Amyloid β peptide aggregation has been accelerated by increasing AChE activity which results in neurodegeneration. 24 In view of these observations, it is therefore inferred that, MELIS prevented neurodegeneration and amyloid beta plaques formation in cerebral cortex by inhibiting AChE activity. Further, persistent amount of ACh was also observed in MELIS-treated AD rats due to inhibition of AChE, which improves the neuronal transmission.…”

Section: Discussionmentioning

confidence: 95%

Anti-Alzheimer’s Activity of Compounds from the Methanolic Extract of Lawsonia inermis Seeds: In vivo and in silico Molecular Docking Studies

Jyothi¹,

Yellamma²

2021

IJPER

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Background: Alzheimer's disease (AD) hallmark feature is neurodegeneration due to the accumulation of β-amyloid plaques and the formation of neurofibrillary tangles in the aged brain. The prevalence of AD in humans is doubled for every two decades and is expected to reach 74.7 million worldwide by 2030. Numerous treatment approaches for AD are currently available but success rate is very limited, therefore novel medicines that minimize AD progression are urgently needed. Methods: In this study, in vivo experiments were performed to test the anti-Alzheimer's property of MELIS on male albino rats under D-galactose induced AD. Estimation of ACh content and AChE activity in cerebral cortex was done in different groups of rats. In addition, in in silico analysis, molecular docking of MELIS compounds against AChE was performed in Auto dock vina software tool. Results: MELIS exhibited Anti-alzheimer's properties in rats by modulating ACh and AChE. Further, in silico molecular docking studies found top 10 MELIS compounds such as Dihydromyricetin, Quercitrin, Zearalenone, Leupeptin, Moricizinesulfone, Lecanoric acid, Sulfamerazine, 3-Deoxyguanosine, N-(3-indolylacetyl)-lisoleucine and Trimethoprim exhibited anti-acetylcholinesterase (AChE) property through showing good binding affinity by forming hydrogen bond interactions with active site amino acids. Conclusion: It is conclude from the results that MELIS compounds exhibit anti-Alzheimer property by modulating the ACh content, AChE activity and interacting to AChE active site amino acids. Therefore MELIS could be preferred source of active compounds for isolation and identification of new drugs for the AD treatment.

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Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP

Abstract: Both HN and AChE can bind Aβ in the absence of added ATP. Addition of ATP increases the binding affinity of Aβ to HN but not to AChE.

Cited by 17 publications

References 107 publications

Differences in the Relative Abundance of ProBDNF and Mature BDNF in A549 and H1299 Human Lung Cancer Cell Media

Differences in the Relative Abundance of ProBDNF and Mature BDNF in A549 and H1299 Human Lung Cancer Cell Media

Regulation of amyloid-β levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells

Anti-Alzheimer’s Activity of Compounds from the Methanolic Extract of Lawsonia inermis Seeds: In vivo and in silico Molecular Docking Studies

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