Most Accessed Articles | Design, Synthesis and Characterization of Novel Urolithin Derivatives as Cholinesterase Inhibitor Agents

Author(s): Maryam Norouzbahari, Emine V. Burgaz, Tugba Ercetin, Amirhossein Fallah, Alireza Foroumadi, Loghman Firoozpour, Mustafa F. Sahin, Mustafa Gazi, Hayrettin O. Gulcan*.

Journal Name: Letters in Drug Design & Discovery

Considering the limitations of current cholinesterase inhibitor drugs for the treatment of Alzheimer’s disease, there is ongoing research activities to find out alternative drug candidates. The aryl-spacer-N-benzyl pharmacophore model has been effectively utilized to design various types of cholinesterase inhibitor molecules, including donepezil. Within this research study, we have questioned the significance of the benzyl group within this pharmacophore employing the urolithin derivatives. Urolithins are benzo[c]chromene analogue metabolites of ellagitannins, abundantly found in pomegranate and berry fruits. Read out full article here:



ARTICLE BY DISEASE – Pathway Crosstalk Analysis based on Signaling Pathway Impact Analysis in Alzheimer’s Disease




Graphical Abstract:





Background: Identifying dysregulated pathways from significant differential expression genes (DEGs) to infer underlying biological insights play an important role in discovering pathogenesis of diseases. However, current pathway-based methods only focus on single pathways in isolation and the analysis of the pathways crosstalk that contains DEGs could improve our understanding of alterations in biological processes.

Objective: To explore the underlying dysregulated pathways of Alzheimer’s disease (AD) efficiently by the crosstalk analysis on both the significant DEGs and the pathways with high contributions.

Method: A novel signaling pathway impact analysis method is used to calculate and rank the signaling pathways of AD. Distance correlation model based on the pathways with ranking contributions is applied to calculate the crosstalk of pathways of AD.

Results: The method not only confirms the presence of known pathways associated with AD including Parkinson’s disease, Vegf signaling pathway and so on but also predicts the presence of unknown pathways such as Basal cell carcinoma and Olfactory transduction pathways that are significantly associated with the onset and deterioration of AD.

Conclusion: The results provide useful supplement and basis for the biological experiments of AD pathogenesis.



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OPEN ACCESS ARTICLE – Technological Solutions for Older People with Alzheimer’s Disease: Review

Journal Name: Current Alzheimer Research

Author(s): Petra Maresova*, Signe Tomsone, Petre Lameski, Joana Madureira, Ana Mendes, Eftim Zdravevski, Ivan Chorbev, Vladimir Trajkovik,Moriah Ellen, Kasper Rodile.




In the nineties, numerous studies began to highlight the problem of the increasing number of people with Alzheimer’s disease in developed countries, especially in the context of demographic progress. At the same time, the 21st century is typical of the development of advanced technologies that penetrate all areas of human life. Digital devices, sensors, and intelligent applications are tools that can help seniors and allow better communication and control of their caregivers. The aim of the paper is to provide an up-to-date summary of the use of technological solutions for improving health and safety for people with Alzheimer’s disease. Firstly, the problems and needs of senior citizens with Alzheimer’s disease (AD) and their caregivers are specified. Secondly, a scoping review is performed regarding the technological solutions suggested to assist this specific group of patients. Works obtained from the following libraries are used in this scoping review: Web of Science, PubMed, Springer, ACM and IEEE Xplore. Four independent reviewers screened the identified records and selected relevant articles which were published in the period from 2007 to 2018. A total of 6,705 publications were selected. In all, 128 full papers were screened. Results obtained from the relevant studies were furthermore divided into the following categories according to the type and use of technologies: devices, processing, and activity recognition. The leading technological solution in the category of devices are wearables and ambient noninvasive sensors. The introduction and utilization of these technologies, however, bring about challenges in acceptability, durability, ease of use, communication, and power requirements. Furthermore, it needs to be pointed out that these technological solutions should be based on open standards.


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EDITORS CHOICE ARTICLE – Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s DiseaseInterplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s Disease

Journal Name: Current Alzheimer Research

Author(s): Martina Zverova, Eva Kitzlerova, Zdenek Fisar*, Roman Jirak, Jana Hroudova, Hana Benakova,Petra Lelkova, Pavel Martasek, Jiri Raboch.




Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders.

Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD.

Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls.

Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD.

Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.



EDITORS CHOICE ARTICLE – Short-Term Response to Cholinesterase Inhibitors in Alzheimer’s Disease Delays Time to Nursing Home Placement

Journal Name: Current Alzheimer Research

Author(s): Carina Wattmo*, Elisabet Londos, Lennart Minthon.




Background: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer’s disease (AD). Whether the individual-specific response directly affects time to nursing home placement (NHP) was not investigated.

Objective: We examined the relationship between the 6-month response to ChEI and institutionalization.

Methods: In a prospective, observational, multi-center study, 881 outpatients with a clinical AD diagnosis and a Mini-Mental State Examination score of 10-26 at the start of ChEI therapy (baseline) were included. The participants were evaluated using cognitive, global, and activities of daily living (ADL) scales at baseline and semiannually over 3 years. The date of NHP was recorded.

Results: During the study, 213 patients (24%) were admitted to nursing homes. The mean ± standard deviation time from baseline (AD diagnosis) to NHP was 20.8 ± 9.3 months. After 6 months of ChEI treatment, the improved/unchanged individuals had longer time to NHP than those who worsened. The prolonged time to NHP was 3 months for cognitive response (P=0.022), 4 months for global response (P=0.004), 6 months for basic ADL response (P<0.001), and 8 months for response in all three scales (P<0.001). No differences were detected between the improved and unchanged groups in any scales.

Conclusion: Patients who exhibit a positive short-term response to ChEI can expect to stay in their own home for 3-8 months longer. These findings underline the importance of a comprehensive clinical examination including various assessment scales to evaluate treatment response and provide a more accurate prognosis.



EDITORS CHOICE ARTICLE – Strategies for Continued Successful Treatment in Patients with Alzheimer’s Disease: An Overview of Switching Between Pharmacological Agents


Author(s): Rafael Blesa, Kazuhiro Toriyama*, Kengo Ueda, Sean Knox, George Grossberg.



Introduction: Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognition and function. Current treatment options for AD include the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, as well as the N-methyl-Daspartate receptor antagonist memantine. Treatment guidelines recommend the use of ChEIs as the standard of care first-line therapy. Several randomized clinical studies have demonstrated the benefits of ChEIs on cognition, global function, behavior and activities of daily living. However, patients may fail to achieve sustained clinical benefits from ChEIs due to lack/loss of efficacy and/or safety, tolerability issues, and poor adherence to the treatment. The purpose of this review is to explore the strategies for continued successful treatment in patients with AD.

Methods: Literature search was performed for articles published in PubMed and MEDLINE, using prespecified search terms. Articles were critically evaluated for inclusion based on their titles, abstracts, and full text of the publication.

Results and Conclusion: The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issues such as lack/loss of efficacy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidence.


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EDITOR’S CHOICE – Mitochondrial Aconitase in Neurodegenerative Disorders

Journal: Current Drug Targets

Author(s): Fariba Khodagholi, Fatemeh Shaerzadeh*, Fateme Montazeri

Graphical Abstract:



Background: Mitochondrial aconitase (Aco2), a member of the family of iron-sulfur [4Fe- 4S]-containing dehydratases, is involved in cellular metabolism through the tricarboxylic acid cycle. Aco2 is highly susceptible to oxidative damage in a way that exposure to the reactive species and free radicals leads to release of iron from the central [4Fe-4S] cluster resulting in the production of the inactive form of Aco2.

Objective: There is increasing evidence supporting a direct association between impaired energy metabolism and the incidence and progression of neurodegenerative disorders in neuronal cells.

Results: It has been shown that alteration in bioenergetic parameters is a common pathological feature of the neurodegenerative diseases leading to neuronal dysfunction. Numerous studies have demonstrated that dysfunctional Aco2, among the other bioenergetic parameters, is a key factor that could promote neurodegeneration.

Conclusion: Increasing our knowledge about energy metabolism-related molecules including Aco2 affected by neurodegenerative disorders might be useful to find an efficient therapeutic strategy for those central nervous system-related diseases. Accordingly, in this review, we have focused on the events and processes that occur in neurodegeneration, leading to the inactivation of Aco2 in the brain.

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EDITOR’S CHOICE – Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy

Journal: Current Alzheimer Research

Author(s): Lingyu Lee*, Yingli Liu


Background: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer’s disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau.

Objective: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau).

Methods: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA.

Results: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA.

Conclusion: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.

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EDITOR’S CHOICE – Up-regulation of DMN Connectivity in Mild Cognitive Impairment Via Network-based Cognitive Training – Current Alzheimer Research

Journal: Current Alzheimer Research

Author(s): Matteo De Marco, Francesca Meneghello, Cristina Pilosio, Jessica Rigon, Annalena Venneri*


Background: Previous work designed a network-based protocol of cognitive training. This programme exploits a mechanism of induced task-oriented co-activation of multiple regions that are part of the default mode network (DMN), to induce functional rewiring and increased functional connectivity within this network.

Objective: In this study, the programme was administered to patients with a diagnosis of mild cognitive impairment to test its effects in a clinical sample.

Method: Twenty-three patients with mild cognitive impairment (mean age: 73.74 years, standard deviation 5.13, female/male ratio 13/10) allocated to the experimental condition, underwent one month of computerised training, while fourteen patients (mean age: 73.14 years, standard deviation 6.16, female/ male ratio 7/7) assigned to the control condition underwent a regime of intense social engagement. Patients were in the prodromal stage of Alzheimer’s disease (AD) as confirmed by clinical follow ups for at least two years. The DMN was computed at baseline and retest, together with other, control patterns of connectivity, grey matter maps and neuropsychological profiles.

Results: A condition-by-timepoint interaction indicating increased connectivity triggered by the programme was found in left parietal DMN regions. No decreases as well as no changes in the other networks or morphology were found. Although between-condition cognitive changes did not reach statistical significance, they correlated positively with changes in DMN connectivity in the left parietal region, supporting the hypothesis that parietal changes were beneficial.

Conclusion: This programme of cognitive training up-regulates a pattern of connectivity which is pathologically down-regulated in AD. We argue that, when cognitive interventions are conceptualised as tools to induce co-activation repeatedly, they can lead to clinically relevant improvements in brain functioning, and can be of aid in support of pharmacological and other interventions in the earliest stages of AD.

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EDITOR’S CHOICE – Every Cloud Has a Silver Lining – CNS & Neurological Disorders – Drug Targets

Journal: CNS & Neurological Disorders – Drug Targets

Author(s): Valeria Bortolotto, Mariagrazia Grilli*

Graphical Abstract:



Background & Objective: Since its initial discovery, current understanding on the functional role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology has impressively grown, especially in consideration of its large ligand repertoire (AGEs, HMGB-1, β amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several chronic human disorders. Downstream RAGE engagement by its ligands, NF-κB signaling activation has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation that in Alzheimer’s Disease (AD) brain expression of RAGE and its ligands is upregulated and that RAGE/NF-κB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD pathophysiology. Herein we review the vast array of information supporting a detrimental role of RAGE/NF-κB axis activation in AD brain and discuss those data in the context of recent findings obtained in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly, the proneurogenic effect resulting from RAGE/NF-κB axis activation could be induced by molecules which are commonly considered as mediators of toxicity, like Aβ oligomers and HMGB-1.

Conclusion: Altogether, despite a large set of data suggesting that RAGE may represent an interesting target for the pharmacological treatment of AD, the complex functional roles of the receptor would require the use of molecules able to counteract RAGE negative effects without altering the positive ones such as the promotion of adult neurogenesis.

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