Life | Special Issue : Alzheimer's Amyloid: Structure, Function, and Disease

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Alzheimer's Amyloid: Structure, Function, and Disease

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Dear Colleagues,

Alzheimer’s disease (AD), a fatal neurodegenerative disease, has puzzled the scientific community for over a century. AD currently affects 50 million patients and is estimated to reach 152 million in 2050. The COVID-19 pandemic may have significantly increased these estimates according to an alarming report showing a hazard ratio of 1.69 for new-onset AD in older people as a late sequel of COVID-19. This may substantially increase the already enormous burden on public health budgets, health care and older people and societies. Therefore, despite the controversial approval of an expensive therapy with aducanumab and expected approval of the use of monoclonal antibodies against β-amyloid, there is an urgent need to find cheap and effective small-molecule treatments for this disease. For this Special Issue, we welcome studies concerning inhibitors of β-amyloid aggregation into oligomers and mature fibrils as well as compounds dissolving mature fibrils. Computational studies docking new compounds to β-amyloid monomers, oligomers and fibrils and molecular dynamics experiments alone or preliminary to “wet” biochemistry leading to elucidation of the mechanism underlying the inhibition of aggregation or dissolution of fibrils are also encouraged.

Dr. Adam Jarmuła
Dr. Dariusz Stępkowski
Guest Editors

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Keywords

Alzheimer’s disease
beta-amyloid
in silico studies
amyloidogenesis
inhibition of fibrillation
dissolution of amyloid fibrils

Published Papers (2 papers)

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Research

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16 pages, 5764 KiB

Open AccessArticle

Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor

by Anushree Chandrashekhar Gade, Manikanta Murahari, Parasuraman Pavadai and Maushmi Shailesh Kumar

Life 2023, 13(6), 1298; https://doi.org/10.3390/life13061298 - 31 May 2023

Cited by 4 | Viewed by 1703

Abstract

Alzheimer’s disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future. Full article

(This article belongs to the Special Issue Alzheimer's Amyloid: Structure, Function, and Disease)

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Review

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28 pages, 7506 KiB

Open AccessReview

Realization of Amyloid-like Aggregation as a Common Cause for Pathogenesis in Diseases

by Soumick Naskar and Nidhi Gour

Life 2023, 13(7), 1523; https://doi.org/10.3390/life13071523 - 7 Jul 2023

Cited by 3 | Viewed by 2396

Abstract

Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide, which causes the formation of plaques and neurofibrillary tangles inside the brain leading to the pathogenesis in Alzheimer’s disease. Subsequently, amyloid-like deposition was found in the etiology of prion diseases, Parkinson’s disease, type II diabetes, and cancer, which was attributed to the aggregation of prion protein, α-Synuclein, islet amyloid polypeptide protein, and p53 protein, respectively. Hence, traditionally amyloids were considered aggregates formed exclusively by proteins or peptides. However, since the last decade, it has been discovered that other metabolites, like single amino acids, nucleobases, lipids, glucose derivatives, etc., have a propensity to form amyloid-like toxic assemblies. Several studies suggest direct implications of these metabolite assemblies in the patho-physiology of various inborn errors of metabolisms like phenylketonuria, tyrosinemia, cystinuria, and Gaucher’s disease, to name a few. In this review, we present a comprehensive literature overview that suggests amyloid-like structure formation as a common phenomenon for disease progression and pathogenesis in multiple syndromes. The review is devoted to providing readers with a broad knowledge of the structure, mode of formation, propagation, and transmission of different extracellular amyloids and their implications in the pathogenesis of diseases. We strongly believe a review on this topic is urgently required to create awareness about the understanding of the fundamental molecular mechanism behind the origin of diseases from an amyloid perspective and possibly look for a common therapeutic strategy for the treatment of these maladies by designing generic amyloid inhibitors. Full article

(This article belongs to the Special Issue Alzheimer's Amyloid: Structure, Function, and Disease)

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