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Special Issue "25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 March 2018

Special Issue Editors

Guest Editor
Dr. Birgit Hutter-Paier

QPS Austria, Parkring 12, 8074 Grambach, Austria
Website | E-Mail
Interests: neurodegeneration; Alzheimer’s disease; pharmacology; animal models of AD
Guest Editor
Dr. Stephan Schilling

Fraunhofer Institute for Cell Therapy and Immunology, Department for Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, Germany
Website | E-Mail
Interests: Alzheimer’s disease; amyloid pathology; pyroGlu Abeta; pharmacology; protein chemistry; immunology

Special Issue Information

Dear Colleagues,

Alzheimer’s Disease (AD) represents the most prevalent neurodegenerative disorder and a serious threat to an aging society. Due to the increasing life expectancy in developing countries, patient numbers will increase multiple-fold within the decades to come. Based on this, AD now represents one of the greatest unmet medical needs. Most of the drugs that are currently in clinical development rely on the amyloid hypothesis, which was first mentioned 25 years ago. Among many others, inhibitors of the beta-secretase BACE, and monoclonal antibodies targeting Aβ, presumably represent the most advanced treatment approaches. However, alternative strategies, which address modified amyloid peptides or their toxicity, are currently being tested. The development of these compounds was accompanied, and significantly advanced, by imaging methods and tracer molecules. This Special Issue aims to provide a platform for reviewing of treatment approaches that are currently being developed, but also welcomes contributions on new molecules for the diagnosis and treatment of AD.  

Dr. Birgit Hutter-Paier
Dr. Stephan Schilling
Guest Editors

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 papers will be 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. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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 hypothesis
  • Alzheimer’s disease
  • pharmacology
  • Amyloid pathology
  • Amyloid toxicity
  • Anti amyloidogenic treatment strategies
  • Amyloid imaging

Published Papers (5 papers)

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Research

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Open AccessArticle Studies for Improving a Rat Model of Alzheimer’s Disease: Icv Administration of Well-Characterized β-Amyloid 1-42 Oligomers Induce Dysfunction in Spatial Memory
Molecules 2017, 22(11), 2007; doi:10.3390/molecules22112007 (registering DOI)
Received: 9 October 2017 / Revised: 7 November 2017 / Accepted: 13 November 2017 / Published: 18 November 2017
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Abstract
During the past 15 years, several genetically altered mouse models of human Alzheimer’s disease (AD) have been developed. These costly models have greatly facilitated the evaluation of novel therapeutic approaches. Injecting synthetic β-amyloid (Aβ) 1-42 species into different parts of the brain of
[...] Read more.
During the past 15 years, several genetically altered mouse models of human Alzheimer’s disease (AD) have been developed. These costly models have greatly facilitated the evaluation of novel therapeutic approaches. Injecting synthetic β-amyloid (Aβ) 1-42 species into different parts of the brain of non-transgenic rodents frequently provided unreliable results, owing to a lack of a genuine characterization of the administered Aβ aggregates. Previously, we have published a new rat AD-model in which protofibrillar-fibrillar Aβ1-42 was administered into rat entorhinal cortex (Sipos 2007). In order to develop a more reliable model, we have injected well-characterized toxic soluble Aβ1-42 species (oligomers, protofibrils and fibrils) intracerebroventricularly (icv) into rat brain. Studies of the distribution of fluorescent-labeled Aβ1-42 in the brain showed that soluble Aβ-species diffused into all parts of the rat brain. After seven days, the Aβ-treated animals showed a significant decrease of spatial memory in Morris water maze test and impairment of synaptic plasticity (LTP) measured in acute hippocampal slices. The results of histological studies (decreased number of viable neurons, increased tau levels and decreased number of dendritic spines) also supported that icv administration of well-characterized toxic soluble Aβ species into rat brain provides a reliable rat AD-model. Full article
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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Open AccessFeature PaperArticle Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease
Molecules 2017, 22(10), 1693; doi:10.3390/molecules22101693
Received: 4 September 2017 / Accepted: 4 October 2017 / Published: 10 October 2017
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Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable
[...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound “D3”, an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice. Full article
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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Open AccessArticle 5-Hydroxycyclopenicillone Inhibits β-Amyloid Oligomerization and Produces Anti-β-Amyloid Neuroprotective Effects In Vitro
Molecules 2017, 22(10), 1651; doi:10.3390/molecules22101651
Received: 16 August 2017 / Revised: 20 September 2017 / Accepted: 29 September 2017 / Published: 1 October 2017
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Abstract
The oligomer of β-amyloid (Aβ) is considered the main neurotoxin in Alzheimer’s disease (AD). Therefore, the inhibition of the formation of Aβ oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission
[...] Read more.
The oligomer of β-amyloid (Aβ) is considered the main neurotoxin in Alzheimer’s disease (AD). Therefore, the inhibition of the formation of Aβ oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission electronic microscopy, it was have discovered that 5-hydroxycyclopenicillone, a cyclopentenone recently isolated from a sponge-associated fungus, effectively reduced the formation of Aβ oligomer from Aβ peptide in vitro. Molecular dynamics simulations suggested hydrophobic interactions between 5-hydroxycyclopenicillone and Aβ peptide, which might prevent the conformational transition and oligomerization of Aβ peptide. Moreover, Aβ oligomer pre-incubated with 5-hydroxycyclopenicillone was less toxic when added to neuronal SH-SY5Y cells compared to the normal Aβ oligomer. Although 5-hydroxycyclopenicillone is not bioavailable in the brain in its current form, further modification or encapsulation of this chemical might improve the penetration of 5-hydroxycyclopenicillone into the brain. Based on the current findings and the anti-oxidative stress properties of 5-hydroxycyclopenicillone, it is suggested that 5-hydroxycyclopenicillone may have potential therapeutic efficacy in treating AD. Full article
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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Review

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Open AccessReview BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer’s Disease Pathology
Molecules 2017, 22(10), 1723; doi:10.3390/molecules22101723
Received: 15 September 2017 / Revised: 9 October 2017 / Accepted: 10 October 2017 / Published: 13 October 2017
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Abstract
Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by increasing loss in memory, cognition, and function of daily living. Among the many pathologic events observed in the progression of AD, changes in amyloid β peptide (Aβ) metabolism proceed fastest, and precede
[...] Read more.
Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by increasing loss in memory, cognition, and function of daily living. Among the many pathologic events observed in the progression of AD, changes in amyloid β peptide (Aβ) metabolism proceed fastest, and precede clinical symptoms. BACE1 (β-secretase 1) catalyzes the initial cleavage of the amyloid precursor protein to generate Aβ. Therefore inhibition of BACE1 activity could block one of the earliest pathologic events in AD. However, therapeutic BACE1 inhibition to block Aβ production may need to be balanced with possible effects that might result from diminished physiologic functions BACE1, in particular processing of substrates involved in neuronal function of the brain and periphery. Potentials for beneficial or consequential effects resulting from pharmacologic inhibition of BACE1 are reviewed in context of ongoing clinical trials testing the effect of BACE1 candidate inhibitor drugs in AD populations. Full article
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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Open AccessReview β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View
Molecules 2017, 22(10), 1692; doi:10.3390/molecules22101692
Received: 15 September 2017 / Revised: 2 October 2017 / Accepted: 6 October 2017 / Published: 10 October 2017
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Abstract
Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid
[...] Read more.
Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca2+-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research. Full article
(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)
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