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Computational Study of Natural Compounds for the Clearance of Amyloid-?eta: A Potential Therapeutic Management Strategy for Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (A?) peptides in senile plaques. The interaction of A? and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream by upgrading the emission of endothelin-1 to induce vasoconstriction. In this process, RAGE is deemed responsible for the influx of A? into the brain through BBB. In the current study, we predicted the interaction potential of the natural compounds vincamine, ajmalicine and emetine with the A? peptide concerned in the treatment of AD against the standard control, curcumin, to validate the A? peptide-compounds results. Protein-protein interaction studies have also been carried out to see their potential to inhibit the binding process of A? and RAGE. Moreover, the current study verifies that ligands are more capable inhibitors of a selected target compared to positive control with reference to ?G values. The inhibition of A? and its interaction with RAGE may be valuable in proposing the next round of lead compounds for effective Alzheimer's disease treatment.

SUBMITTER: Ahmad SS

PROVIDER: S-EPMC6767296 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Computational Study of Natural Compounds for the Clearance of Amyloid-Βeta: A Potential Therapeutic Management Strategy for Alzheimer's Disease.

Ahmad Syed Sayeed SS Khan Haroon H Danish Rizvi Syed Mohd SM Ansari Siddique Akber SA Ullah Riaz R Rastrelli Luca L Mahmood Hafiz Majid HM Siddiqui Mohd Haris MH

Molecules (Basel, Switzerland) 20190905 18

Alzheimer's disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aβ) peptides in senile plaques. The interaction of Aβ and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream ...[more]

PMID: 31491967

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Project description:BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAβ42 + /amyR - = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A - T - and in CSFAβ42 + /amyR - , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A - T - (β = 0.58; p < 0.001), CSFAβ42 + /amyR - (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Project description:Opioids are widely used for treating different types of pains, but overuse and abuse of prescription opioids have led to opioid epidemic in the United States. Besides analgesic effects, chronic use of opioid can also cause tolerance, dependence, and even addiction. Effective treatment of opioid addiction remains a big challenge today. Studies on addictive effects of opioids focus on striatum, a main component in the brain responsible for drug dependence and addiction. Some transcription regulators have been associated with opioid addiction, but relationship between analgesic effects of opioids and dependence behaviors mediated by them at the molecular level has not been thoroughly investigated. In this paper, we developed a new computational strategy that identifies novel targets and potential therapeutic molecular compounds for opioid dependence and addiction. We employed several statistical and machine learning techniques and identified differentially expressed genes over time which were associated with dependence-related behaviors after exposure to either morphine or heroin, as well as potential transcription regulators that regulate these genes, using time course gene expression data from mouse striatum. Moreover, our findings revealed that some of these dependence-associated genes and transcription regulators are known to play key roles in opioid-mediated analgesia and tolerance, suggesting that an intricate relationship between opioid-induce pain-related pathways and dependence may develop at an early stage during opioid exposure. Finally, we determined small compounds that can potentially target the dependence-associated genes and transcription regulators. These compounds may facilitate development of effective therapy for opioid dependence and addiction. We also built a database (http://daportals.org) for all opioid-induced dependence-associated genes and transcription regulators that we discovered, as well as the small compounds that target those genes and transcription regulators.

Dataset Information

Computational Study of Natural Compounds for the Clearance of Amyloid-?eta: A Potential Therapeutic Management Strategy for Alzheimer's Disease.

Publications

Computational Study of Natural Compounds for the Clearance of Amyloid-Βeta: A Potential Therapeutic Management Strategy for Alzheimer's Disease.

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