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Amyloids and Neurological Diseases
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Amyloids and Neurological Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 5440

Special Issue Editor

Dr. Byunghee Henry Han

E-Mail Website
Guest Editor
Department of Pharmacology, AT Still University in Health Sciences, Kirksville, MO 63501, USA
Interests: Alzheimer’s disease; cerebral amyloid angiopathy; dementia; cerebrovascular dysfunction; small vessel disorder; amyloid-beta; amyloid aggregation and disaggregation; amyloid imaging; amyloid clearance; oxidative stress; nuclear receptors; scavenger receptors; polyphenols; flavonoids; antioxidants; neuroprotection; drug discovery

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to our Special Issue of the International Journal of Molecular Sciences (IJMS), entitled “Amyloids and Neurological Diseases”. This issue will cover a selection of recent research topics and current review articles, reporting the latest updates on amyloid pathogenesis and related neurological diseases.

Several peptides and proteins possess amino acid sequences that are prone to convert from their native physiological conformation into toxic aggregates. Misfolded, pathologically altered proteins (amyloids) form deposits in distinctive regions of the human central nervous system (CNS) in increasingly common neurodegenerative diseases (NDDs), such as Alzheimer’s, Parkinson’s, and prion diseases. We welcome papers that address the roles of amyloidogenic proteins in disease and normal physiology and papers that evaluate the interaction between these different amyloidogenic proteins. Related to disease, these could include (but are not limited to) how amyloidosis is associated with neurodegenerative diseases such as Alzheimer’s disease and prion disorders. Importantly, we are also interested in papers that investigate recent advances in determining structures of amyloidogenic proteins and the impact this has had on understanding disease and developing therapeutics. This could include the challenges involved in developing treatments against amyloid disorders, as well as advances in state-of-the-art techniques being utilized for drug discovery and therapeutic development.

This Special Issue is now open for submissions. If you are interested in contributing your work, please send a short abstract or tentative title to the Guest editor or Editorial Office.

Dr. Byunghee Henry Han
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • amyloid
  • protein misfolding
  • protein structure
  • amyloid aggregation and disaggregation
  • neurodegenerative disease
  • neuroprotection
  • drug discovery

Published Papers (2 papers)

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Research

35 pages, 8493 KiB  
Article
Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease
by Galina F. Makhaeva, Nadezhda V. Kovaleva, Elena V. Rudakova, Natalia P. Boltneva, Maria V. Grishchenko, Sofya V. Lushchekina, Tatiana Y. Astakhova, Olga G. Serebryakova, Elena N. Timokhina, Ekaterina F. Zhilina, Evgeny V. Shchegolkov, Mariya V. Ulitko, Eugene V. Radchenko, Vladimir A. Palyulin, Yanina V. Burgart, Victor I. Saloutin, Sergey O. Bachurin and Rudy J. Richardson
Int. J. Mol. Sci. 2023, 24(3), 2285; https://doi.org/10.3390/ijms24032285 - 24 Jan 2023
Cited by 7 | Viewed by 3019
Abstract
A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) [...] Read more.
A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a–c, intermediate for salicylimines 10a–c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure–activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD. Full article
(This article belongs to the Special Issue Amyloids and Neurological Diseases)
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16 pages, 16060 KiB  
Article
Amentoflavone Promotes Cellular Uptake and Degradation of Amyloid-Beta in Neuronal Cells
by Byung Hee Han, Brooke Cofell, Emily Everhart, Courtney Humpal, Sam-Sik Kang, Sang Kook Lee and Jeong Sook Kim-Han
Int. J. Mol. Sci. 2022, 23(11), 5885; https://doi.org/10.3390/ijms23115885 - 24 May 2022
Cited by 5 | Viewed by 1726
Abstract
Deposition of fibrillar forms of amyloid β-protein (Aβ) is commonly found in patients with Alzheimer’s disease (AD) associated with cognitive decline. Impaired clearance of Aβ species is thought to be a major cause of late-onset sporadic AD. Aβ secreted into the extracellular milieu [...] Read more.
Deposition of fibrillar forms of amyloid β-protein (Aβ) is commonly found in patients with Alzheimer’s disease (AD) associated with cognitive decline. Impaired clearance of Aβ species is thought to be a major cause of late-onset sporadic AD. Aβ secreted into the extracellular milieu can be cleared from the brain through multiple pathways, including cellular uptake in neuronal and non-neuronal cells. Recent studies have showed that the naturally-occurring polyphenol amentoflavone (AMF) exerts anti-amyloidogenic effects. However, its effects on metabolism and cellular clearance of Aβ remain to be tested. In the present study, we demonstrated that AMF significantly increased the cellular uptake of both Aβ1-40 and Aβ1-42, but not inverted Aβ42-1 in mouse neuronal N2a cells. Though AMF promoted internalization of cytotoxic Aβ1-42, it significantly reduced cell death in our assay condition. Our data further revealed that the internalized Aβ is translocated to lysosomes and undergoes enzymatic degradation. The saturable kinetic of Aβ uptake and our pharmacologic experiments showed the involvement of receptor-mediated endocytosis, in part, through the class A scavenger receptors as a possible mechanism of action of AMF. Taken together, our findings indicate that AMF can lower the levels of extracellular Aβ by increasing their cellular uptake and clearance, suggesting the therapeutic potential of AMF for the treatment of AD. Full article
(This article belongs to the Special Issue Amyloids and Neurological Diseases)
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