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Molecular Mechanism of Alzheimer's Disease III

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 51978

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Prof. Dr. Ian Macreadie

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School of Science, RMIT University, Bundoora West Campus, PO Box 71, Bundoora, VIC 3083, Australia
Interests: Alzheimer’s disease; yeast models; ageing; stress responses; drug mechanisms; drug resistance; microbial genomics
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Special Issue Information

Dear Colleagues,

This Special Issue is the third volume of our previous Special Issue "Molecular Mechanism of Alzheimer's Disease" and "Molecular Mechanism of Alzheimer's Disease II". Alzheimer’s disease (AD) is an age-related neurological disease that affects tens of millions of people and their carers worldwide. Hallmark features of AD include plaques composed of amyloid beta, as well as neurofibrillary tangles of tau protein. However, despite more than a century of research, the cause of AD remains inconclusive. The roles of amyloid beta and tau are being investigated, and other causes of AD are now under consideration. The contributions of researchers, model organisms, and various hypotheses will be examined in this Special Issue.

Prof. Dr. Ian Macreadie
Guest Editor

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Keywords

Alzheimer’s disease
amyloid beta
brain cholesterol
brain microbes
neurofibrillary tangles
neurodegeneration
neuroinflammation
oxidative stress
proteostasis
tau
type 3 diabetes

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 190 KiB

Open AccessEditorial

Molecular Mechanisms of Alzheimer’s Disease III

by Ian G. Macreadie

Int. J. Mol. Sci. 2022, 23(24), 15876; https://doi.org/10.3390/ijms232415876 - 14 Dec 2022

Viewed by 1726

Abstract

This Special Issue of IJMS is the third in the series: Molecular Mechanisms of Alzheimer’s Disease [...] Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

Research

Jump to: Editorial, Review

10 pages, 1170 KiB

Open AccessCommunication

Differential Effects of Endocannabinoids on Amyloid-Beta Aggregation and Toxicity

by Marzie Khavandi, Praveen P. N. Rao and Michael A. Beazely

Int. J. Mol. Sci. 2023, 24(2), 911; https://doi.org/10.3390/ijms24020911 - 4 Jan 2023

Cited by 10 | Viewed by 2039

Abstract

The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer’s disease (AD), which is characterized by amyloid β (Aβ) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aβ aggregation and protect cells against Aβ toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aβ42 aggregation. They were able to provide protection against Aβ42 induced cytotoxicity via receptor-mediated and non-receptor-mediated mechanisms in CB1-CHO and HT22 cells, respectively. The aggregation kinetic experiments demonstrate the anti-Aβ aggregation activity of some endocannabinoids (AEA, noladin). These data demonstrate the potential role and application of endocannabinoids in AD pathology and treatment. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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14 pages, 2572 KiB

Open AccessArticle

Trans-Chalcone Plus Baicalein Synergistically Reduce Intracellular Amyloid Beta (Aβ₄₂) and Protect from Aβ₄₂ Induced Oxidative Damage in Yeast Models of Alzheimer’s Disease

by Sudip Dhakal, Paul A. Ramsland, Benu Adhikari and Ian Macreadie

Int. J. Mol. Sci. 2021, 22(17), 9456; https://doi.org/10.3390/ijms22179456 - 31 Aug 2021

Cited by 19 | Viewed by 3086

Abstract

Finding an effective therapeutic to prevent or cure AD has been difficult due to the complexity of the brain and limited experimental models. This study utilized unmodified and genetically modified Saccharomyces cerevisiae as model organisms to find potential natural bioactive compounds capable of reducing intracellular amyloid beta 42 (Aβ₄₂) and associated oxidative damage. Eleven natural bioactive compounds including mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans-chalcone were screened for their ability to reduce intracellular green fluorescent protein tagged Aβ₄₂ (GFP-Aβ₄₂) levels. The two most effective compounds from the screens were combined in varying concentrations of each to study the combined capacity to reduce GFP-Aβ₄₂. The most effective combinations were examined for their effect on growth rate, turnover of native Aβ₄₂ and reactive oxygen species (ROS). The bioactive compounds except mangiferin and urolithin A significantly reduced intracellular GFP-Aβ₄₂ levels. Baicalein and trans-chalcone were the most effective compounds among those that were screened. The combination of baicalein and trans-chalcone synergistically reduced GFP-Aβ₄₂ levels. A combination of 15 μM trans-chalcone and 8 μM baicalein was found to be the most synergistic combination. The combination of the two compounds significantly reduced ROS and Aβ₄₂ levels in yeast cells expressing native Aβ₄₂ without affecting growth of the cells. These findings suggest that the combination of baicalein and trans-chalcone could be a promising multifactorial therapeutic strategy to cure or prevent AD. However, further studies are recommended to look for similar cytoprotective activity in humans and to find an optimal dosage. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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14 pages, 2461 KiB

Open AccessArticle

Identifying the Main Functional Pathways Associated with Cognitive Resilience to Alzheimer’s Disease

by Marta Pérez-González, Sara Badesso, Elena Lorenzo, Elizabeth Guruceaga, Alberto Pérez-Mediavilla, Ana García-Osta and Mar Cuadrado-Tejedor

Int. J. Mol. Sci. 2021, 22(17), 9120; https://doi.org/10.3390/ijms22179120 - 24 Aug 2021

Cited by 16 | Viewed by 2676

Abstract

Understanding the mechanisms involved in cognitive resilience in Alzheimer’s disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4⁺ cells in the brain as a key player of cognitive dysfunction in AD. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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21 pages, 2482 KiB

Open AccessArticle

Whole Blood Transcriptome Characterization of 3xTg-AD Mouse and Its Modulation by Transcranial Direct Current Stimulation (tDCS)

by Chiara Magri, Erika Vitali, Sara Cocco, Edoardo Giacopuzzi, Marco Rinaudo, Paolo Martini, Alessandro Barbon, Claudio Grassi and Massimo Gennarelli

Int. J. Mol. Sci. 2021, 22(14), 7629; https://doi.org/10.3390/ijms22147629 - 16 Jul 2021

Cited by 4 | Viewed by 3046

Abstract

The 3xTg-AD mouse is a widely used model in the study of Alzheimer’s Disease (AD). It has been extensively characterized from both the anatomical and behavioral point of view, but poorly studied at the transcriptomic level. For the first time, we characterize the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluate how its gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that represent a direct signature of the genetic background of the mouse. Moreover, in the 6-month-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD symptomatology onset. Finally, tDCS was associated with gene expression changes in the 3xTg-AD, but not in the control mice. In conclusion, this study provides an in-depth molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatment effects. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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11 pages, 1425 KiB

Open AccessArticle

Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional and Longitudinal Investigation

by Pratishtha Chatterjee, Michelle Tegg, Steve Pedrini, Anne M. Fagan, Chengjie Xiong, Abhay K. Singh, Kevin Taddei, Samantha Gardener, Colin L. Masters, Peter R. Schofield, Gerhard Multhaup, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Steven M. Greenberg, Mark A. van Buchem, Erik Stoops, Hugo Vanderstichele, Charlotte E. Teunissen, Graeme J. Hankey, Marieke J. H. Wermer, Hamid R. Sohrabi, Ralph N. Martins and the Dominantly Inherited Alzheimer Network Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(6), 2931; https://doi.org/10.3390/ijms22062931 - 13 Mar 2021

Cited by 13 | Viewed by 3712

Abstract

Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001; Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001; Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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16 pages, 1466 KiB

Open AccessArticle

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

by Jamieson B. Mcdonald, Sudip Dhakal and Ian Macreadie

Int. J. Mol. Sci. 2021, 22(4), 1835; https://doi.org/10.3390/ijms22041835 - 12 Feb 2021

Cited by 17 | Viewed by 3738

Abstract

Alzheimer’s disease (AD), the most prevalent, age-related, neurodegenerative disease, is associated with the accumulation of amyloid beta (Aβ) and oxidative stress. However, the sporadic nature of late-onset AD has suggested that other factors, such as aluminium may be involved. Aluminium (Al³⁺) is the most ubiquitous neurotoxic metal on earth, extensively bioavailable to humans. Despite this, the link between Al³⁺ and AD has been debated for decades and remains controversial. Using Saccharomyces cerevisiae as a model organism expressing Aβ42, this study aimed to examine the mechanisms of Al³⁺ toxicity and its interactions with Aβ42. S. cerevisiae cells producing Aβ42 treated with varying concentrations of Al³⁺ were examined for cell viability, growth inhibition, and production of reactive oxygen species (ROS). Al³⁺ caused a significant reduction in cell viability: cell death in yeast producing green fluorescent protein tagged with Aβ42 (GFP–Aβ42) was significantly higher than in cells producing green fluorescent protein (GFP) alone. Additionally, Al³⁺ greatly inhibited the fermentative growth of yeast producing GFP–Aβ42, which was enhanced by ferric iron (Fe³⁺), while there was negligible growth inhibition of GFP cells. Al³⁺- induced ROS levels in yeast expressing native Aβ42 were significantly higher than in empty vector controls. These findings demonstrate Al³⁺ has a direct, detrimental toxic synergy with Aβ42 that can be influenced by Fe³⁺, causing increased oxidative stress. Thus, Al³⁺ should be considered as an important factor, alongside the known characteristic hallmarks of AD, in the development and aetiology of the disease. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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Review

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35 pages, 1564 KiB

Open AccessReview

Zebrafish as a Potential Model for Neurodegenerative Diseases: A Focus on Toxic Metals Implications

by Emanuela Paduraru, Diana Iacob, Viorica Rarinca, Gabriel Plavan, Dorel Ureche, Roxana Jijie and Mircea Nicoara

Int. J. Mol. Sci. 2023, 24(4), 3428; https://doi.org/10.3390/ijms24043428 - 8 Feb 2023

Cited by 22 | Viewed by 4512

Abstract

In the last century, industrial activities increased and caused multiple health problems for humans and animals. At this moment, heavy metals are considered the most harmful substances for their effects on organisms and humans. The impact of these toxic metals, which have no biological role, poses a considerable threat and is associated with several health problems. Heavy metals can interfere with metabolic processes and can sometimes act as pseudo-elements. The zebrafish is an animal model progressively used to expose the toxic effects of diverse compounds and to find treatments for different devastating diseases that human beings are currently facing. This review aims to analyse and discuss the value of zebrafish as animal models used in neurological conditions, such as Alzheimer’s disease (AD), and Parkinson’s disease (PD), particularly in terms of the benefits of animal models and the limitations that exist. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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22 pages, 992 KiB

Open AccessReview

Comprehensive Review Regarding Mercury Poisoning and Its Complex Involvement in Alzheimer’s Disease

by Emanuela Paduraru, Diana Iacob, Viorica Rarinca, Angelica Rusu, Roxana Jijie, Ovidiu-Dumitru Ilie, Alin Ciobica, Mircea Nicoara and Bogdan Doroftei

Int. J. Mol. Sci. 2022, 23(4), 1992; https://doi.org/10.3390/ijms23041992 - 11 Feb 2022

Cited by 22 | Viewed by 12036

Abstract

Mercury (Hg) is considered one of the most widespread toxic environmental pollutants, which seems to have multiple effects on organisms even at low concentrations. It has a critical role in many health problems with harmful consequences, with Hg primarily targeting the brain and its components, such as the central nervous system (CNS). Hg exposure was associated with numerous CNS disorders that frequently trigger Alzheimer’s disease (AD). Patients with AD have higher concentrations of Hg in blood and brain tissue. This paper aims to emphasize a correlation between Hg and AD based on the known literature in the occupational field. The outcome shows that all these concerning elements could get attributed to Hg. However, recent studies did not investigate the molecular level of Hg exposure in AD. The present review highlights the interactions between Hg and AD in neuronal degenerations, apoptosis, autophagy, oxidative stress (OS), mitochondrial malfunctions, gastrointestinal (GI) microflora, infertility and altering gene expression. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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27 pages, 3541 KiB

Open AccessReview

Elevating the Levels of Calcium Ions Exacerbate Alzheimer’s Disease via Inducing the Production and Aggregation of β-Amyloid Protein and Phosphorylated Tau

by Pei-Pei Guan, Long-Long Cao and Pu Wang

Int. J. Mol. Sci. 2021, 22(11), 5900; https://doi.org/10.3390/ijms22115900 - 31 May 2021

Cited by 49 | Viewed by 6003

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with a high incidence rate. The main pathological features of AD are β-amyloid plaques (APs), which are formed by β-amyloid protein (Aβ) deposition, and neurofibrillary tangles (NFTs), which are formed by the excessive phosphorylation of the tau protein. Although a series of studies have shown that the accumulation of metal ions, including calcium ions (Ca²⁺), can promote the formation of APs and NFTs, there is no systematic review of the mechanisms by which Ca²⁺ affects the development and progression of AD. In view of this, the current review summarizes the mechanisms by which Ca²⁺ is transported into and out of cells and organelles, such as the cell, endoplasmic reticulum, mitochondrial and lysosomal membranes to affect the balance of intracellular Ca²⁺ levels. In addition, dyshomeostasis of Ca²⁺ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aβ peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca²⁺ can affect the learning ability and memory of people with AD. In addition, the effects of these mechanisms on the synaptic plasticity are also discussed. Finally, the molecular network through which Ca²⁺ regulates the pathogenesis of AD is introduced, providing a theoretical basis for improving the clinical treatment of AD. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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28 pages, 8045 KiB

Open AccessReview

The Neurovascular Unit Dysfunction in Alzheimer’s Disease

by Luis O. Soto-Rojas, Mar Pacheco-Herrero, Paola A. Martínez-Gómez, B. Berenice Campa-Córdoba, Ricardo Apátiga-Pérez, Marcos M. Villegas-Rojas, Charles R. Harrington, Fidel de la Cruz, Linda Garcés-Ramírez and José Luna-Muñoz

Int. J. Mol. Sci. 2021, 22(4), 2022; https://doi.org/10.3390/ijms22042022 - 18 Feb 2021

Cited by 76 | Viewed by 7758

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease III)

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