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Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and...
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Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 38029

Special Issue Editor

Dr. Farid Rahimi

E-Mail Website
Guest Editor
Division of Biomedical Science and Biochemistry, Research School of Biology, ANU College of Science, The Australian National University, Canberra, ACT 2600, Australia
Interests: S100 calcium-binding proteins in inflammation, atherosclerosis, and alzheimer disease; atherosclerosis, alzheimer disease; S100A8, S100A9, S100A12 and inflammation; protein-misfolding diseases; neurodegeneration; alzheimer disease pathology, aetiology, and relevant controversies; mechanisms underlying the pathogenesis of Alzheimer disease; amyloid β-protein; RNA and DNA aptamers; aptamers against amyloidogenic proteins; cell metabolism and inflammation in cancer

Special Issue Information

Dear Colleagues,

Dementia comprises a collection of memory and behavioural symptoms that can be caused by different brain afflictions. Common dementias include Alzheimer disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, Creutzfeldt–Jakob disease, and Huntington disease. Alzheimer disease (AD) is the most common, accounting for ~70% of dementia cases.

AD is a predominant, devastating, progressive chronic disease that begins as episodic memory lapses and progresses to changes in mood and personality and a decline of mental capacities. AD typically afflicts patients in their eighth or ninth decade of life, and its incidence rises steeply after 65 years of age. The global statistics on AD prevalence are ominous, and the 2018 cost of care is projected to be billions in the US alone. The emotional and spiritual costs to any family of a patient with dementia are immeasurable and irrecompensable. Such forbidding statistics has established AD as a profoundly disconcerting and very costly global health crisis.

Despite the grim statistics, research into AD has been progressing strongly, and has generated a vast body of literature since the original description of AD in 1901 by Alois Alzheimer. Given the vast AD literature and AD’s burden on societies globally, the cumulative, expansive, and sometimes confusing body of literature on AD calls for selective, critical, and in-depth assessment of the accumulated literature before designing, undertaking, or publishing purposeful, worthwhile and cutting-edge studies. Different, and sometimes, conflicting theories about the aetiology of AD abound, while multiple clinical trials based on predominant theories of the aetiology of AD have so far failed to produce effective treatments.

The aims of this Special Issue are to 1) highlight controversies or shortcomings of basic scientific research into AD so to help refocus research endeavours tackling AD; 2) collect reviews or original research articles that would potentially link the various theories on the aetiology and pathogenesis of AD and provide potentially unifying theories; and 3) collect analyses or discussions of the various reasons why so many clinical trials based on predominant theories of AD have failed so far.

Dr. Farid Rahimi
Guest Editor

Manuscript Submission Information

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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. Biomedicines 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 2600 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

  • Alzheimer disease
  • Alzheimer-type dementia
  • Senile dementia
    • Amyloid β-protein
    • Animal models
    • Basic science
    • Biomarkers
    • Clinical trials
    • Clinics
    • Cost of care
    • Diagnosis
    • Diagnostics
    • Aetiology
    • Hypotheses
    • Pathogenesis
    • Therapeutics
    • Therapy
    • Translational medicine

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Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 171 KiB  
Editorial
Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials
by Farid Rahimi
Biomedicines 2021, 9(3), 254; https://doi.org/10.3390/biomedicines9030254 - 5 Mar 2021
Cited by 4 | Viewed by 2239
Abstract
Dementia comprises a collection of cognitive and sensory symptoms, including memory loss, communication difficulties, difficulty in planning and problem solving, disorientation and confusion, compromised olfaction, loss of visual perception, agnosia; and psychological symptoms, including personality and behavioral changes, depression, anxiety, hallucination, mood swings, [...] Read more.
Dementia comprises a collection of cognitive and sensory symptoms, including memory loss, communication difficulties, difficulty in planning and problem solving, disorientation and confusion, compromised olfaction, loss of visual perception, agnosia; and psychological symptoms, including personality and behavioral changes, depression, anxiety, hallucination, mood swings, agitation, and apathy [...] Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)

Research

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10 pages, 1741 KiB  
Article
Tyramine and Amyloid Beta 42: A Toxic Synergy
by Sudip Dhakal and Ian Macreadie
Biomedicines 2020, 8(6), 145; https://doi.org/10.3390/biomedicines8060145 - 30 May 2020
Cited by 18 | Viewed by 4445
Abstract
Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be [...] Read more.
Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer’s disease. This study aimed to examine whether tyramine could be involved in AD pathology by using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. These findings indicate that there can be a detrimental synergy between Aβ42 and tyramine, which could be considered in Alzheimer’s disease. This work also demonstrates the utility of yeast as a model for studying toxic agents such as Aβ42, tyramine, and agents that might exacerbate AD pathology. Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)
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12 pages, 1681 KiB  
Article
Exposure to CuO Nanoparticles Mediates NFκB Activation and Enhances Amyloid Precursor Protein Expression
by Xiaoyang Mou, Alexander Pilozzi, Breeya Tailor, Jing Yi, Catherine Cahill, Jack Rogers and Xudong Huang
Biomedicines 2020, 8(3), 45; https://doi.org/10.3390/biomedicines8030045 - 27 Feb 2020
Cited by 14 | Viewed by 3215
Abstract
Amyloid precursor protein (APP) is directly related to Aβ amyloidosis—a hallmark of Alzheimer’s disease (AD). However, the impact of environmental factors upon APP biology and Aβ amyloid pathology have not been well studied. The increased use of nanoparticles (NPs) or engineered nanomaterials (ENMs) [...] Read more.
Amyloid precursor protein (APP) is directly related to Aβ amyloidosis—a hallmark of Alzheimer’s disease (AD). However, the impact of environmental factors upon APP biology and Aβ amyloid pathology have not been well studied. The increased use of nanoparticles (NPs) or engineered nanomaterials (ENMs) has led to a growing body of evidence suggesting that exposure to metal/metal oxide NPs, such as Fe2O3, CuO, and ZnO, may contribute to the pathophysiology of neurodegenerative diseases such as AD through neuroinflammation. Our previous studies indicated that exposure to CuO nanoparticles (CuONPs) induce potent in vitro neurotoxicity. Herein, we investigated the effects on APP expression in neuronal cells exposed to different metal oxide NPs. We found a low dose of CuONPs effectively activated the NFκB signaling pathway and increased APP expression. Moreover, the inhibition of p65 expression using siRNA abolished CuONP-mediated APP expression, suggesting that NFκB-regulated APP expression in response to CuONP exposure may be associated with AD pathology. Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)
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Review

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20 pages, 3297 KiB  
Review
Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer’s Disease
by Md. Ataur Rahman, Md Saidur Rahman, MD. Hasanur Rahman, Mohammad Rasheduzzaman, ANM Mamun-Or-Rashid, Md Jamal Uddin, Md Rezanur Rahman, Hongik Hwang, Myung-Geol Pang and Hyewhon Rhim
Biomedicines 2021, 9(1), 5; https://doi.org/10.3390/biomedicines9010005 - 24 Dec 2020
Cited by 44 | Viewed by 10998
Abstract
Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which [...] Read more.
Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD. Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)
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19 pages, 3618 KiB  
Review
Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease
by Charles R Joseph
Biomedicines 2020, 8(7), 228; https://doi.org/10.3390/biomedicines8070228 - 20 Jul 2020
Cited by 15 | Viewed by 4378
Abstract
With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood–brain barrier (BBB) breakdown occurring early in the AD process [...] Read more.
With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood–brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates. Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)
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16 pages, 565 KiB  
Review
Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research
by Konstantina G. Yiannopoulou, Aikaterini I. Anastasiou, Venetia Zachariou and Sygkliti-Henrietta Pelidou
Biomedicines 2019, 7(4), 97; https://doi.org/10.3390/biomedicines7040097 - 9 Dec 2019
Cited by 191 | Viewed by 11692
Abstract
Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. [...] Read more.
Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies. Full article
(This article belongs to the Special Issue Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials)
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