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25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease

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

Deadline for manuscript submissions: closed (30 March 2018) | Viewed by 101501

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Dr. Birgit Hutter-Paier

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Guest Editor

QPS Austria, Grambach, Austria
Interests: Alzheimer’s disease; Parkinson’s disease; lysosomal storage diseases; aging; dementia
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Stephan Schilling

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Guest Editor

1. Head of Department of Drug Design and Target Validation, Anhalt University of Applied Sciences, Köthen, Germany
2. Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany
Interests: Alzheimer’s disease; amyloidosis; drug development; antibodies; enzyme inhibition
Special Issues, Collections and Topics in MDPI journals

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

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Keywords

Amyloid hypothesis
Alzheimer’s disease
pharmacology
Amyloid pathology
Amyloid toxicity
Anti amyloidogenic treatment strategies
Amyloid imaging

Published Papers (14 papers)

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22 pages, 5454 KiB

Open AccessArticle

A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta

by Silvia Hilt, Robin Altman, Tamás Kálai, Izumi Maezawa, Qizhi Gong, Sebastian Wachsmann-Hogiu, Lee-Way Jin and John C. Voss

Molecules 2018, 23(8), 2010; https://doi.org/10.3390/molecules23082010 - 12 Aug 2018

Cited by 15 | Viewed by 5655

Abstract

There is growing recognition regarding the role of intracellular amyloid beta (Aβ) in the Alzheimer’s disease process, which has been linked with aberrant signaling and the disruption of protein degradation mechanisms. Most notably, intraneuronal Aβ likely underlies the oxidative stress and mitochondrial dysfunction that have been identified as key elements of disease progression. In this study, we employed fluorescence imaging to explore the ability of a bifunctional small molecule to reduce aggregates of intracellular Aβ and attenuate oxidative stress. Structurally, this small molecule is comprised of a nitroxide spin label linked to an amyloidophilic fluorene and is known as spin-labeled fluorene (SLF). The effect of the SLF on intracellular Aβ accumulation and oxidative stress was measured in MC65 cells, a human neuronal cell line with inducible expression of the amyloid precursor protein and in the N2a neuronal cell line treated with exogenous Aβ. Super-resolution microscopy imaging showed SLF decreases the accumulation of intracellular Aβ. Confocal microscopy imaging of MC65 cells treated with a reactive oxygen species (ROS)-sensitive dye demonstrated SLF significantly reduces the intracellular Aβ-induced ROS signal. In order to determine the contributions of the separate SLF moieties to these protective activities, experiments were also carried out on cells with nitroxides lacking the Aβ targeting domain or fluorene derivatives lacking the nitroxide functionality. The findings support a synergistic effect of SLF in counteracting both the conformational toxicity of both endogenous and exogenous Aβ, its promotion of ROS, and Aβ metabolism. Furthermore, these studies demonstrate an intimate link between ROS production and Aβ oligomer formation. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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10 pages, 1630 KiB

Open AccessCommunication

Antibodies towards Tyrosine Amyloid-Like Fibrils Allow Toxicity Modulation and Cellular Imaging of the Assemblies

by Dor Zaguri, Topaz Kreiser, Shira Shaham-Niv and Ehud Gazit

Molecules 2018, 23(6), 1273; https://doi.org/10.3390/molecules23061273 - 26 May 2018

Cited by 28 | Viewed by 4219

Abstract

The amino acid tyrosine forms cytotoxic amyloid-like fibrils by molecular self-assembly. However, the production of antibodies towards tyrosine assemblies, reflecting their presentation to the immune system, was not demonstrated yet. Here, we describe the production of antibodies that specifically recognize tyrosine in its fibrillated form. The antibodies were demonstrated to specifically bind self-assembled tyrosine, in contrast to its non-aggregated form or disintegrated fibrils. The antibodies could be used for immunostaining of tyrosine fibrils in cultured cells. Furthermore, confocal microscopy allowed a demonstration of the intracellular presence of the metabolite amyloids in a neuroblastoma cell model. Finally, pre-incubation of tyrosine fibrils with the antibodies resulted in significant reduction in their cytotoxicity. Taken together, we provide an experimental proof for the immunogenicity of tyrosine amyloid fibrillary assemblies. These specific antibodies against tyrosine structures could be further used as a research tool to study the dynamics, toxicity and cellular localization of the assemblies. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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17 pages, 47356 KiB

Open AccessArticle

Immunohistochemical Evidence from APP-Transgenic Mice for Glutaminyl Cyclase as Drug Target to Diminish pE-Abeta Formation

by Maike Hartlage-Rübsamen, Alexandra Bluhm, Anke Piechotta, Miriam Linnert, Jens-Ulrich Rahfeld, Hans-Ulrich Demuth, Inge Lues, Peer-Hendrik Kuhn, Stefan F. Lichtenthaler, Steffen Roßner and Corinna Höfling

Molecules 2018, 23(4), 924; https://doi.org/10.3390/molecules23040924 - 17 Apr 2018

Cited by 12 | Viewed by 5680

Abstract

Oligomeric assemblies of neurotoxic amyloid beta (Abeta) peptides generated by proteolytical processing of the amyloid precursor protein (APP) play a key role in the pathogenesis of Alzheimer’s disease (AD). In recent years, a substantial heterogeneity of Abeta peptides with distinct biophysical and cell biological properties has been demonstrated. Among these, a particularly neurotoxic and disease-specific Abeta variant is N-terminally truncated and modified to pyroglutamate (pE-Abeta). Cell biological and animal experimental studies imply the catalysis of this modification by the enzyme glutaminyl cyclase (QC). However, direct histopathological evidence in transgenic animals from comparative brain region and cell type-specific expression of transgenic hAPP and QC, on the one hand, and on the formation of pE-Abeta aggregates, on the other, is lacking. Here, using single light microscopic, as well as triple immunofluorescent, labeling, we report the deposition of pE-Abeta only in the brain regions of APP-transgenic Tg2576 mice with detectable human APP and endogenous QC expression, such as the hippocampus, piriform cortex, and amygdala. Brain regions showing human APP expression without the concomitant presence of QC (the anterodorsal thalamic nucleus and perifornical nucleus) do not display pE-Abeta plaque formation. However, we also identified brain regions with substantial expression of human APP and QC in the absence of pE-Abeta deposition (the Edinger-Westphal nucleus and locus coeruleus). In these brain regions, the enzymes required to generate N-truncated Abeta peptides as substrates for QC might be lacking. Our observations provide additional evidence for an involvement of QC in AD pathogenesis via QC-catalyzed pE-Abeta formation. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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7082 KiB

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

by Ágnes Kasza, Botond Penke, Zsuzsanna Frank, Zsolt Bozsó, Viktor Szegedi, Ákos Hunya, Klaudia Németh, Gábor Kozma and Lívia Fülöp

Molecules 2017, 22(11), 2007; https://doi.org/10.3390/molecules22112007 - 18 Nov 2017

Cited by 52 | Viewed by 8460

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 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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1014 KiB

Open AccessFeature PaperArticle

Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease

by Janine Kutzsche, Sarah Schemmert, Markus Tusche, Jörg Neddens, Roland Rabl, Dagmar Jürgens, Oleksandr Brener, Antje Willuweit, Birgit Hutter-Paier and Dieter Willbold

Molecules 2017, 22(10), 1693; https://doi.org/10.3390/molecules22101693 - 10 Oct 2017

Cited by 26 | Viewed by 4590

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 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 (APP_SL), 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 APP_SL mice. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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2141 KiB

Open AccessArticle

5-Hydroxycyclopenicillone Inhibits β-Amyloid Oligomerization and Produces Anti-β-Amyloid Neuroprotective Effects In Vitro

by Jiaying Zhao, Fufeng Liu, Chunhui Huang, Jieyi Shentu, Minjun Wang, Chenkai Sun, Liping Chen, Sicheng Yan, Fang Fang, Yuanyuan Wang, Shujun Xu, C. Benjamin Naman, Qinwen Wang, Shan He and Wei Cui

Molecules 2017, 22(10), 1651; https://doi.org/10.3390/molecules22101651 - 01 Oct 2017

Cited by 10 | Viewed by 5312

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 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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13 pages, 248 KiB

Open AccessReview

Network Medicine for Alzheimer’s Disease and Traditional Chinese Medicine

by Juliet T. Jarrell, Li Gao, David S. Cohen and Xudong Huang

Molecules 2018, 23(5), 1143; https://doi.org/10.3390/molecules23051143 - 11 May 2018

Cited by 47 | Viewed by 8006

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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14 pages, 512 KiB

Open AccessFeature PaperReview

Passive Aβ Immunotherapy: Current Achievements and Future Perspectives

by Stephan Schilling, Jens-Ulrich Rahfeld, Inge Lues and Cynthia A. Lemere

Molecules 2018, 23(5), 1068; https://doi.org/10.3390/molecules23051068 - 03 May 2018

Cited by 36 | Viewed by 7368

Abstract

Passive immunotherapy has emerged as a very promising approach for the treatment of Alzheimer’s disease and other neurodegenerative disorders, which are characterized by the misfolding and deposition of amyloid peptides. On the basis of the amyloid hypothesis, the majority of antibodies in clinical development are directed against amyloid β (Aβ), the primary amyloid component in extracellular plaques. This review focuses on the current status of Aβ antibodies in clinical development, including their characteristics and challenges that came up in clinical trials with these new biological entities (NBEs). Emphasis is placed on the current view of common side effects observed with passive immunotherapy, so-called amyloid-related imaging abnormalities (ARIAs), and potential ways to overcome this issue. Among these new ideas, a special focus is placed on molecules that are directed against post-translationally modified variants of the Aβ peptide, an emerging approach for development of new antibody molecules. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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14 pages, 999 KiB

Open AccessReview

A Systematic Review of Antiamyloidogenic and Metal-Chelating Peptoids: Two Structural Motifs for the Treatment of Alzheimer’s Disease

by Sherri C. Young

Molecules 2018, 23(2), 296; https://doi.org/10.3390/molecules23020296 - 31 Jan 2018

Cited by 11 | Viewed by 5463

Abstract

Alzheimer’s disease (AD) is an incurable form of dementia affecting millions of people worldwide and costing billions of dollars in health care-related payments, making the discovery of a cure a top health, societal, and economic priority. Peptide-based drugs and immunotherapies targeting AD-associated beta-amyloid (Aβ) aggregation have been extensively explored; however, their therapeutic potential is limited by unfavorable pharmacokinetic (PK) properties. Peptoids (N-substituted glycine oligomers) are a promising class of peptidomimetics with highly tunable secondary structures and enhanced stabilities and membrane permeabilities. In this review, the biological activities, structures, and physicochemical properties for several amyloid-targeting peptoids will be described. In addition, metal-chelating peptoids with the potential to treat AD will be discussed since there are connections between the dysregulation of certain metals and the amyloid pathway. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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23 pages, 1029 KiB

Open AccessFeature PaperReview

Iridoids and Other Monoterpenes in the Alzheimer’s Brain: Recent Development and Future Prospects

by Solomon Habtemariam

Molecules 2018, 23(1), 117; https://doi.org/10.3390/molecules23010117 - 07 Jan 2018

Cited by 38 | Viewed by 9398

Abstract

Iridoids are a class of monoterpenoid compounds constructed from 10-carbon skeleton of isoprene building units. These compounds in their aglycones and glycosylated forms exist in nature to contribute to mechanisms related to plant defenses and diverse plant-animal interactions. Recent studies have also shown that iridoids and other structurally related monoterpenes display a vast array of pharmacological effects that make them potential modulators of the Alzheimer’s disease (AD). This review critically evaluates the therapeutic potential of these natural products by assessing key in vitro and in vivo data published in the scientific literature. Mechanistic approach of scrutiny addressing their effects in the Alzheimer’s brain including the τ-protein phosphorylation signaling, amyloid beta (Aβ) formation, aggregation, toxicity and clearance along with various effects from antioxidant to antiinflammatory mechanisms are discussed. The drug likeness of these compounds and future prospects to consider in their development as potential leads are addressed. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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3448 KiB

Open AccessReview

Amyloid Biomarkers in Conformational Diseases at Face Value: A Systematic Review

by Maria Fernanda Avila-Vazquez, Nelly F. Altamirano-Bustamante and Myriam M. Altamirano-Bustamante

Molecules 2018, 23(1), 79; https://doi.org/10.3390/molecules23010079 - 29 Dec 2017

Cited by 7 | Viewed by 5670

Abstract

Conformational diseases represent a new aspect of proteomic medicine where diagnostic and therapeutic paradigms are evolving. In this context, the early biomarkers for target cell failure (neurons, β-cells, etc.) represent a challenge to translational medicine and play a multidimensional role as biomarkers and potential therapeutic targets. This systematic review, which follows the PICO and Prisma methods, analyses this new-fangled multidimensionality, its strengths and limitations, and presents the future possibilities it opens up. The nuclear diagnosis methods are immunoassays: ELISA, immunodot, western blot, etc., while the therapeutic approach is focused on pharmaco- and molecular chaperones. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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947 KiB

Open AccessReview

BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer’s Disease Pathology

by Gerald Koelsch

Molecules 2017, 22(10), 1723; https://doi.org/10.3390/molecules22101723 - 13 Oct 2017

Cited by 89 | Viewed by 11631

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 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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2028 KiB

Open AccessReview

β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View

by Botond Penke, Ferenc Bogár and Lívia Fülöp

Molecules 2017, 22(10), 1692; https://doi.org/10.3390/molecules22101692 - 10 Oct 2017

Cited by 79 | Viewed by 14789

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 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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14 pages, 1404 KiB

Open AccessCommentary

Synaptic Alterations in Mouse Models for Alzheimer Disease—A Special Focus on N-Truncated Abeta 4-42

by Katharina Dietrich, Yvonne Bouter, Michael Müller and Thomas A. Bayer

Molecules 2018, 23(4), 718; https://doi.org/10.3390/molecules23040718 - 21 Mar 2018

Cited by 18 | Viewed by 4433

Abstract

This commentary reviews the role of the Alzheimer amyloid peptide Aβ on basal synaptic transmission, synaptic short-term plasticity, as well as short- and long-term potentiation in transgenic mice, with a special focus on N-terminal truncated Aβ_4-42. Aβ_4-42 is highly abundant in the brain of Alzheimer’s disease (AD) patients. It demonstrates increased neurotoxicity compared to full length Aβ, suggesting an important role in the pathogenesis of AD. Transgenic Tg4-42 mice, a model for sporadic AD, express human Aβ_4-42 in Cornu Ammonis (CA1) neurons, and develop age-dependent hippocampal neuron loss and neurological deficits. In contrast to other transgenic AD mouse models, the Tg4-42 model exhibits synaptic hyperexcitability, altered synaptic short-term plasticity with no alterations in short- and long-term potentiation. The outcomes of this study are discussed in comparison with controversial results from other AD mouse models. Full article

(This article belongs to the Special Issue 25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease)

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25th Anniversary of the Amyloid Hypothesis and Alzheimer Disease

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