Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer's Disease.

Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aß) aggregation and impaired synaptic transmission, which makes the associated proteins, such as ß-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of Rosmarinus officinalis, ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.

Methylphenidate and Rosmarinus officinalis improves cognition and regulates inflammation and synaptic gene expression in AlCl3-induced neurotoxicity mouse model.

Methylphenidate (MPH), a psychotropic medication is commonly used for children with attention deficit hyperactivity disorder (ADHD). In this study we elucidated the neuroprotective and anti-inflammatory effects of MPH and Rosmarinus officinalis (rosemary) extract, an ancient aromatic herb with several applications in traditional medicine. Briefly, six groups of mice (n = 8 each group), were specified for the study and behavioral analysis was performed to analyze spatial memory followed by histological assessment and gene expression analysis of synaptic (Syn I, II and III) and inflammatory markers (IL-6, TNFα and GFAP) via qRT-PCR, in an AlCl3-induced mouse model for neurotoxicity. The behavioral analysis demonstrated significant cognitive decline, memory defects and altered gene expression in AlCl3-treated group. Rosemary extract significantly decreased the expression of inflammatory and synaptic markers to the similar levels as that of MPH. The present findings suggested the neuroprotective potential of Rosmarinus officinalis extract. However, further characterization of its anti-inflammatory and neuroprotective properties and MPH is required to strategize future treatments for several neurological and neurodegenerative disorders, including Alzheimer's disease.

An in silico approach to identify potential downstream targets of miR-153 involved in Alzheimer's disease.

Background: In recent years, microRNAs (miRNAs) have emerged as key players in the pathophysiology of multiple diseases including Alzheimer's disease (AD). Messenger RNA (mRNA) targeting for regulation of gene expression by miRNAs has been implicated in the annotation of disease pathophysiology as well as in the explication of their starring role in contemporary therapeutic interventions. One such miRNA is miR-153 which mediates the survival of cortical neurons and inhibits plaque formation. However, the core mRNA targets of miR-153 have not been fully illustrated. Objective: The present study aimed to elucidate the potential involvement of miR-153 in AD pathogenesis and to reveal its downstream targets. Methods: miRanda was used to identify AD-associated targets of miR-153. TargetScan, PicTar, miRmap, and miRDB were further used to validate these targets. STRING 12 was employed to assess the protein-protein interaction network while Gene ontology (GO) analysis was carried out to identify the molecular functions exhibited by these gene targets. Results: In silico analysis using miRanda predicted five important AD-related targets of miR-153, including APP, SORL1, PICALM, USF1, and PSEN1. All five target genes are negatively regulated by miR-153 and are substantially involved in AD pathogenesis. A protein interaction network using STRING 12 uncovered 30 potential interacting partners for SORL1, PICALM, and USF1. GO analysis revealed that miR-153 target genes play a critical role in neuronal survival, differentiation, exon guidance, amyloid precursor protein processing, and synapse formation. Conclusion: These findings unravel the potential role of miR-153 in the pathogenesis of AD and provide the basis for forthcoming experimental studies.

A quantitative meta-analysis of vitamin C in the pathophysiology of Alzheimer's disease.

Purpose: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with many complex pathways feeding into its pathogenesis and progression. Vitamin C, an essential dietary antioxidant, is vital for proper neurological development and maintenance. This meta-analysis and systematic review attempted to define the relationship between vitamin C plasma levels and AD while highlighting the importance and involvement of vitamin C in the pathogenesis of AD. Materials and methods: PRISMA guidelines were used to obtain studies quantifying the plasma levels of vitamin C in AD and control subjects. The literature was searched in the online databases PubMed, Google Scholar, and Web of Science. A total of 12 studies were included (n = 1,100) and analyzed using Comprehensive Meta-Analysis 3.0. Results: The results show that there is a significant decrease in the plasma vitamin C levels of AD patients as compared to healthy controls (pooled SMD with random-effect model: -1.164, with 95%CI: -1.720 to -0.608, Z = -4.102, p = 0.00) with significant heterogeneity (I 2 = 93.218). The sensitivity analysis showed directionally similar results. Egger's regression test (p = 0.11) and visual inspection of the funnel plot showed no publication bias. Conclusion: Based on these studies, it can be deduced that the deficiency of vitamin C is involved in disease progression and supplementation is a plausible preventive and treatment strategy. However, clinical studies are warranted to elucidate its exact mechanistic role in AD pathophysiology and prevention.

Rosmarinus officinalis and Methylphenidate Exposure Improves Cognition and Depression and Regulates Anxiety-Like Behavior in AlCl3-Induced Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurological illness that causes severe cognitive impairment. AD patients also experience at least one of the neuropsychiatric symptoms including apathy, depression, and anxiety during the course of their life. Acetylcholine esterase inhibitors are the available treatment options to alleviate cognitive deficits, whereas methylphenidate (MPH), a psychostimulant, is considered for the treatment of apathy in AD patients. Rosmarinus officinalis, a perennial herb, has been potentially known to have antioxidant and anti-inflammatory properties. The present study investigated the potential effects of MPH and R. officinalis in comparison with the standard drug, Donepezil, on cognition, anxiety, and depression in the AlCl3-induced mouse model of AD. The animals were divided into eight groups (n = 8, each). The results revealed that the MPH- and R. officinalis-treated groups significantly improved memory impairment, whereas R. officinalis substantially reduced depression and anxiety as compared with other treatment groups. MPH treatment induced an antidepressant effect and increased anxiety-like behavior. Moreover, the AlCl3 exposure led to the formation of amyloid beta (Aß) plaques in mice hippocampus; however, none of the tested drugs caused a significant reduction in amyloid burden at the selected doses. The present study suggested the potential of R. officinalis to improve memory as well as neuropsychiatric symptoms in AD. Although R. officinalis improved cognitive abilities, it did not reduce the amyloid plaque burden, which indicates that the memory-enhancing effects of R. officinalis are due to some alternate mechanism that needs to be explored further.

Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aß1-42-induced mouse model of Alzheimer's disease.

BACKGROUND: Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation. PURPOSE AND STUDY DESIGN: The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aß1-42-induced mouse model of AD. METHODS: BALB/c mice were divided into ten groups. Half were injected with Aß1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis. RESULTS: The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aß1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid. CONCLUSION: Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aß1-42-induced neurotoxicity in AD.

Amyloid-beta Induced Neurotoxicity Impairs Cognition and Adult Hippocampal Neurogenesis in a Mouse Model for Alzheimer's Disease.

BACKGROUND: Neurogenesis, the key mechanism to generate new neurons from existing stem cell niches continues throughout the life in the adult mammalian brain, although decelerate with aging or the progression of neurodegenerative disorders like Alzheimer's disease (AD). In the past few years, impaired adult hippocampal neurogenesis emerged as a contributing hallmark of AD pathophysiology along with amyloid beta (Aß) and tau hyper phosphorylation-induced neurotoxicity. However, no conclusive evidence exists that indicates the up/down-regulation of adult hippocampal neurogenesis during the course of AD progression. METHODS: In this study, we examined alterations in adult hippocampal neurogenesis and cognitive deficits using Aß(1-42)-induced mouse model of AD. RESULTS: Our results demonstrate that Aß administration induces an anxiety like behavior and impairs spatial and non-spatial memory and learning in BALB/c mice. Extensive neuronal loss was also evident in the dentate gyrus (DG), CA1, CA2 and CA3 regions of hippocampus in Aß-treated animals. Furthermore, Aß-exposure markedly reduced the real-time expression of markers of cell proliferation and migration i.e. Ki67 and DCX, whereas immunohistochemistry analysis revealed a substantial reduction in the expression levels of Ki67 and NeuN. CONCLUSION: Our findings highlight the association of Aß-induced neurotoxicity with altered neurogenesis and memory formation; however further insight is warranted to explore the underlying molecular pathway(s). Moreover, the treatment strategies aiming to repair the adult hippocampal neurogenesis hold potential as AD therapeutics.

Data integration for functional annotation of regulatory single nucleotide polymorphisms associated with Alzheimer's disease susceptibility.

BACKGROUND: Alzheimer's disease (AD), the most common form of dementia affects 24.3 million people worldwide. More than twenty genetic loci have been associated with AD and a significant number of genetic variants were mapped within these loci. A large proportion of genome wide significant variants lie outside the coding region. However, the plausible function of these variants is still unexplored. OBJECTIVE: The present study aimed to unravel the regulatory role of proxy single nucleotide polymorphisms (SNPs), to determine their risk of developing AD. METHODS: The RegulomeDB was employed to predict the regulatory role of proxy SNPs. Protein association network and functional enrichment analysis was performed using String10.5 and gene ontology, respectively. RESULTS: A total of 451 SNPs were examined through SNAP web portal (r2 ≤ 0.80) which returned 2186 proxy SNPs in linkage disequilibrium (LD) with genome wide significant SNPs for AD. Out of 2186 SNPs analyzed in RegulomeDB, 151 had the scores < 3 that indicates the high degree of their potential regulatory function. Further analysis revealed that out of these 151 SNPs, 37 were genome wide significant for AD, 17 were significantly associated with diseases other than AD, 89 were proxy SNPs (not genome wide significant) for various diseases including AD while 8 SNPs were novel proxy SNPs for AD. CONCLUSION: These findings support the notion that the non-coding variants can be strongly associated with disease risk. Further validation through genome wide association studies will be helpful for the elucidation of their regulatory potential.