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15 pages, 3067 KiB

Open AccessArticle

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

by Elena Salobrar-García, Ana C. Rodrigues-Neves, Ana I. Ramírez, Rosa de Hoz, José A. Fernández-Albarral, Inés López-Cuenca, José M. Ramírez, António F. Ambrósio and Juan J. Salazar

Int. J. Mol. Sci. 2020, 21(3), 816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030816 - 27 Jan 2020

Cited by 27 | Viewed by 4109

Abstract

Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown [...] Read more.

Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice. Full article

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

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10 pages, 2957 KiB

Open AccessCommunication

NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain

by Motaz M. Fadul, Claire J. Garwood, Rachel Waller, Navonna Garrett, Paul R. Heath, Fiona E Matthews, Carol Brayne, Stephen B. Wharton and Julie E. Simpson

Int. J. Mol. Sci. 2020, 21(1), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010340 - 04 Jan 2020

Cited by 4 | Viewed by 3411

Abstract

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific [...] Read more.

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8⁺ neurofibrillary tangles (p = 0.001) and CD68⁺ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response. Full article

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

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20 pages, 2881 KiB

Open AccessArticle

Network Medicine Approach for Analysis of Alzheimer’s Disease Gene Expression Data

by David Cohen, Alexander Pilozzi and Xudong Huang

Int. J. Mol. Sci. 2020, 21(1), 332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010332 - 03 Jan 2020

Cited by 10 | Viewed by 2861

Abstract

Alzheimer’s disease (AD) is the most widespread diagnosed cause of dementia in the elderly. It is a progressive neurodegenerative disease that causes memory loss as well as other detrimental symptoms that are ultimately fatal. Due to the urgent nature of this disease, and [...] Read more.

Alzheimer’s disease (AD) is the most widespread diagnosed cause of dementia in the elderly. It is a progressive neurodegenerative disease that causes memory loss as well as other detrimental symptoms that are ultimately fatal. Due to the urgent nature of this disease, and the current lack of success in treatment and prevention, it is vital that different methods and approaches are applied to its study in order to better understand its underlying mechanisms. To this end, we have conducted network-based gene co-expression analysis on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. By processing and filtering gene expression data taken from the blood samples of subjects with varying disease states and constructing networks based on that data to evaluate gene relationships, we have been able to learn about gene expression correlated with the disease, and we have identified several areas of potential research interest. Full article

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

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12 pages, 1604 KiB

Open AccessArticle

Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast

by Sudip Dhakal, Mishal Subhan, Joshua M. Fraser, Kenneth Gardiner and Ian Macreadie

Int. J. Mol. Sci. 2019, 20(14), 3531; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143531 - 19 Jul 2019

Cited by 24 | Viewed by 3933

Abstract

A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the [...] Read more.

A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aβ42 turnover. In this study the proportion of cells having GFP fused to Aβ after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aβ42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aβ42 fused to GFP. The levels of native Aβ42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aβ42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aβ42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance. Full article

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

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Review

Jump to: Research

20 pages, 1353 KiB

Open AccessReview

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

by Joanne Elizabeth Rowles, Kevin Noel Keane, Thiago Gomes Heck, Vinicius Cruzat, Giuseppe Verdile and Philip Newsholme

Int. J. Mol. Sci. 2020, 21(21), 8204; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218204 - 02 Nov 2020

Cited by 12 | Viewed by 4601

Abstract

Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features [...] Read more.

Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD. Full article

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

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45 pages, 3307 KiB

Open AccessReview

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

by Sudip Dhakal and Ian Macreadie

Int. J. Mol. Sci. 2020, 21(21), 8014; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218014 - 28 Oct 2020

Cited by 16 | Viewed by 4069

Abstract

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. [...] Read more.

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD. Full article

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

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19 pages, 1345 KiB

Open AccessReview

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

by Sharmeelavathi Krishnan, Yasaswi Shrestha, Dona P. W. Jayatunga, Sarah Rea, Ralph Martins and Prashant Bharadwaj

Int. J. Mol. Sci. 2020, 21(18), 6739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186739 - 14 Sep 2020

Cited by 22 | Viewed by 3899

Abstract

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). [...] Read more.

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment. Full article

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

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37 pages, 691 KiB

Open AccessReview

Lipids and Alzheimer’s Disease

by Yu-Chia Kao, Pei-Chuan Ho, Yuan-Kun Tu, I-Ming Jou and Kuen-Jer Tsai

Int. J. Mol. Sci. 2020, 21(4), 1505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041505 - 22 Feb 2020

Cited by 238 | Viewed by 17099

Abstract

Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such [...] Read more.

Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics. Full article

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

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23 pages, 930 KiB

Open AccessReview

Neuroinflammation and Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

by Pi-Shan Sung, Po-Yu Lin, Chi-Hung Liu, Hui-Chen Su and Kuen-Jer Tsai

Int. J. Mol. Sci. 2020, 21(3), 701; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030701 - 21 Jan 2020

Cited by 105 | Viewed by 9304

Abstract

In adult brain, new neurons are generated throughout adulthood in the subventricular zone and the dentate gyrus; this process is commonly known as adult neurogenesis. The regulation or modulation of adult neurogenesis includes various intrinsic pathways (signal transduction pathway and epigenetic or genetic [...] Read more.

In adult brain, new neurons are generated throughout adulthood in the subventricular zone and the dentate gyrus; this process is commonly known as adult neurogenesis. The regulation or modulation of adult neurogenesis includes various intrinsic pathways (signal transduction pathway and epigenetic or genetic modulation pathways) or extrinsic pathways (metabolic growth factor modulation, vascular, and immune system pathways). Altered neurogenesis has been identified in Alzheimer’s disease (AD), in both human AD brains and AD rodent models. The exact mechanism of the dysregulation of adult neurogenesis in AD has not been completely elucidated. However, neuroinflammation has been demonstrated to alter adult neurogenesis. The presence of various inflammatory components, such as immune cells, cytokines, or chemokines, plays a role in regulating the survival, proliferation, and maturation of neural stem cells. Neuroinflammation has also been considered as a hallmark neuropathological feature of AD. In this review, we summarize current, state-of-the art perspectives on adult neurogenesis, neuroinflammation, and the relationship between these two phenomena in AD. Furthermore, we discuss the potential therapeutic approaches, focusing on the anti-inflammatory and proneurogenic interventions that have been reported in this field. Full article

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

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