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19 pages, 3580 KiB

Open AccessArticle

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

by Mohamed Haddad, Morgane Perrotte, Mohamed Raâfet Ben Khedher, Clément Demongin, Aurélie Lepage, Tamás Fülöp and Charles Ramassamy

Int. J. Mol. Sci. 2019, 20(19), 4906; https://doi.org/10.3390/ijms20194906 - 3 Oct 2019

Cited by 29 | Viewed by 5022

Abstract

Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was [...] Read more.

Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer’s disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ peptide, pTau T181 and alpha-synuclein were quantified by luminex assay. Treatment of neuronal cells with MG or GO reduced the cellular levels of NSE, PRGN, APP, MMP-9 and ANGPTL-4 and the nEVs levels of BDNF, PRGN and LCN2. Our findings suggest that targeting MG and GO may be a promising therapeutic strategy to prevent or delay the progression of AD. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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14 pages, 3747 KiB

Open AccessArticle

Interleukin-4 and Interleukin-13 Exacerbate Neurotoxicity of Prothrombin Kringle-2 in Cortex In Vivo via Oxidative Stress

by Jae Yeong Jeong, Young Cheul Chung and Byung Kwan Jin

Int. J. Mol. Sci. 2019, 20(8), 1927; https://doi.org/10.3390/ijms20081927 - 19 Apr 2019

Cited by 24 | Viewed by 3966

Abstract

The present study investigated the effects of activated microglia-derived interleukin-4 (IL-4) and IL-13 on neurodegeneration in prothrombin kringle-2 (pKr-2)-treated rat cortex. pKr-2 was unilaterally injected into the Sprague–Dawley rat cerebral cortex and IL-4 and IL-13 neutralizing antibody was used to block the function [...] Read more.

The present study investigated the effects of activated microglia-derived interleukin-4 (IL-4) and IL-13 on neurodegeneration in prothrombin kringle-2 (pKr-2)-treated rat cortex. pKr-2 was unilaterally injected into the Sprague–Dawley rat cerebral cortex and IL-4 and IL-13 neutralizing antibody was used to block the function of IL-4 and IL-13. Immunohistochemical analysis showed a significant loss of NeuN⁺ and Nissl⁺ cells and an increase of OX-42⁺ cells in the cortex at seven days post pKr-2. The levels of IL-4 and IL-13 expression were upregulated in the activated microglia as early as 12 hours post pKr-2 and sustained up to seven days post pKr-2. Neutralization by IL-4 or IL-13 antibodies (NA) significantly increased neuronal survival in pKr-2-treated rat cortex in vivo by suppressing microglial activation and the production of reactive oxygen species, as analyzed by immunohisotochemistry and hydroethidine histochemistry. These results suggest that IL-4 and IL-13 that were endogenously expressed from reactive microglia may play a critical role on neuronal death by regulating oxidative stress during the neurodegenerative diseases, such as Alzheimer’s disease and dementia. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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21 pages, 3150 KiB

Open AccessArticle

Preliminary Study on Clusterin Protein (sCLU) Expression in PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish) AβPP genes Affected by Non-Steroid Isoprenoids and Water-Soluble Cholesterol

by Beata Pająk, Elżbieta Kania, Anita Gołaszewska and Arkadiusz Orzechowski

Int. J. Mol. Sci. 2019, 20(6), 1481; https://doi.org/10.3390/ijms20061481 - 24 Mar 2019

Cited by 4 | Viewed by 3619

Abstract

In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AβPP) processing and regulates clusterin protein levels. AβPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor [...] Read more.

In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AβPP) processing and regulates clusterin protein levels. AβPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor alpha (sAβPPα) presence in AβPP-wt cells and Aβ expression in AβPP-sw cells. Nerve growth factor (NGF)-differentiated rat neuronal pheochromocytoma PC-12 cells were untreated/treated with statins alone or together with non-sterol isoprenoids. Co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol demonstrated statin-dependent neurotoxicity resulted from the attenuated activity of mevalonate pathway rather than lower cholesterol level. Atorvastatin (50 μM) or simvastatin (50 μM) as well as cholesterol chelator methyl-β-cyclodextrin (0.2 mM) diminished cell viability (p < 0.05) and clusterin levels. Interestingly, co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol stimulated (p < 0.05) clusterin expression. Effects of non-sterol isoprenoids, but not water soluble cholesterol (Chol-PEG), were the most significant in mock-transfected cells. Geranylgeraniol (GGOH) overcame atorvastatin (ATR)-dependent cytotoxicity. This effect does not seem to be dependent on clusterin, as its level became lower after GGOH. The novelty of these findings is that they show that the mevalonate (MEV) pathway rather than cholesterol itself plays an important role in clusterin expression levels. In mock-transfected, rather than in AβPP-overexpressing cells, GGOH/farnesol (FOH) exerted a protective effect. Thus, protein prenylation with GGOH/FOH might play substantial role in neuronal cell survival. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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16 pages, 1494 KiB

Open AccessCommunication

Selection of Membrane RNA Aptamers to Amyloid Beta Peptide: Implications for Exosome-Based Antioxidant Strategies

by Teresa Janas, Karolina Sapoń, Michael H. B. Stowell and Tadeusz Janas

Int. J. Mol. Sci. 2019, 20(2), 299; https://doi.org/10.3390/ijms20020299 - 13 Jan 2019

Cited by 17 | Viewed by 5227

Abstract

The distribution of amyloid beta peptide 42 (Aβ42) between model exosomal membranes and a buffer solution was measured. The model membranes contained liquid-ordered regions or phosphatidylserine. Results demonstrated that up to ca. 20% of amyloid peptide, generated in the plasma (or intracellular) membrane [...] Read more.

The distribution of amyloid beta peptide 42 (Aβ42) between model exosomal membranes and a buffer solution was measured. The model membranes contained liquid-ordered regions or phosphatidylserine. Results demonstrated that up to ca. 20% of amyloid peptide, generated in the plasma (or intracellular) membrane as a result of proteolytic cleavage of amyloid precursor proteins by β- and γ-secretases, can stay within the membrane milieu. The selection of RNA aptamers that bind to Aβ42 incorporated into phosphatidylserine-containing liposomal membranes was performed using the selection-amplification (SELEX) method. After eight selection cycles, the pool of RNA aptamers was isolated and its binding to Aβ42-containing membranes was demonstrated using the gel filtration method. Since membranes can act as a catalytic surface for Aβ42 aggregation, these RNA aptamers may inhibit the formation of toxic amyloid aggregates that can permeabilize cellular membranes or disrupt membrane receptors. Strategies are proposed for using functional exosomes, loaded with RNA aptamers specific to membrane Aβ42, to reduce the oxidative stress in Alzheimer’s disease and Down’s syndrome. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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Review

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17 pages, 1337 KiB

Open AccessReview

Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases

by Fabrice Collin

Int. J. Mol. Sci. 2019, 20(10), 2407; https://doi.org/10.3390/ijms20102407 - 15 May 2019

Cited by 570 | Viewed by 19279

Abstract

Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of [...] Read more.

Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of products of lipid, protein and DNA oxidation in vivo. Even if they participate in cell signaling and metabolism regulation, ROS are also formidable weapons against most of the biological materials because of their intrinsic nature. By nature too, neurons are particularly sensitive to oxidation because of their high polyunsaturated fatty acid content, weak antioxidant defense and high oxygen consumption. Thus, the overproduction of ROS in neurons appears as particularly deleterious and the mechanisms involved in oxidative degradation of biomolecules are numerous and complexes. This review highlights the production and regulation of ROS, their chemical properties, both from kinetic and thermodynamic points of view, the links between them, and their implication in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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20 pages, 3631 KiB

Open AccessReview

Crosstalk between Oxidative Stress and Tauopathy

by Md. Mamunul Haque, Dhiraj P. Murale, Yun Kyung Kim and Jun-Seok Lee

Int. J. Mol. Sci. 2019, 20(8), 1959; https://doi.org/10.3390/ijms20081959 - 22 Apr 2019

Cited by 53 | Viewed by 6412

Abstract

Tauopathy is a collective term for neurodegenerative diseases associated with pathological modifications of tau protein. Tau modifications are mediated by many factors. Recently, reactive oxygen species (ROS) have attracted attention due to their upstream and downstream effects on tauopathy. In physiological conditions, healthy [...] Read more.

Tauopathy is a collective term for neurodegenerative diseases associated with pathological modifications of tau protein. Tau modifications are mediated by many factors. Recently, reactive oxygen species (ROS) have attracted attention due to their upstream and downstream effects on tauopathy. In physiological conditions, healthy cells generate a moderate level of ROS for self-defense against foreign invaders. Imbalances between ROS and the anti-oxidation pathway cause an accumulation of excessive ROS. There is clear evidence that ROS directly promotes tau modifications in tauopathy. ROS is also highly upregulated in the patients’ brain of tauopathies, and anti-oxidants are currently prescribed as potential therapeutic agents for tauopathy. Thus, there is a clear connection between oxidative stress (OS) and tauopathies that needs to be studied in more detail. In this review, we will describe the chemical nature of ROS and their roles in tauopathy. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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23 pages, 873 KiB

Open AccessReview

Extracellular Vesicle as a Source of Alzheimer’s Biomarkers: Opportunities and Challenges

by Seongju Lee, Sakulrat Mankhong and Ju-Hee Kang

Int. J. Mol. Sci. 2019, 20(7), 1728; https://doi.org/10.3390/ijms20071728 - 8 Apr 2019

Cited by 86 | Viewed by 9278

Abstract

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by memory decline and cognitive dysfunction. Although the primary causes of AD are not clear, it is widely accepted that the accumulation of amyloid beta (Aβ) and consecutive hyper-phosphorylation of tau, synaptic loss, [...] Read more.

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by memory decline and cognitive dysfunction. Although the primary causes of AD are not clear, it is widely accepted that the accumulation of amyloid beta (Aβ) and consecutive hyper-phosphorylation of tau, synaptic loss, oxidative stress and neuronal death might play a vital role in AD pathogenesis. Recently, it has been widely suggested that extracellular vesicles (EVs), which are released from virtually all cell types, are a mediator in regulating AD pathogenesis. Clinical evidence for the diagnostic performance of EV-associated biomarkers, particularly exosome biomarkers in the blood, is also emerging. In this review, we briefly introduce the biological function of EVs in the central nervous system and discuss the roles of EVs in AD pathogenesis. In particular, the roles of EVs associated with autophagy and lysosomal degradation systems in AD proteinopathy and in disease propagation are discussed. Next, we summarize candidates for biochemical AD biomarkers in EVs, including proteins and miRNAs. The accumulating data brings hope that the application of EVs will be helpful for early diagnostics and the identification of new therapeutic targets for AD. However, at the same time, there are several challenges in developing valid EV biomarkers. We highlight considerations for the development of AD biomarkers from circulating EVs, which includes the standardization of pre-analytical sources of variability, yield and purity of isolated EVs and quantification of EV biomarkers. The development of valid EV AD biomarkers may be facilitated by collaboration between investigators and the industry. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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24 pages, 3921 KiB

Open AccessReview

Bridging the Gap between Alzheimer’s Disease and Alzheimer’s-like Diseases in Animals

by Anita Gołaszewska, Wojciech Bik, Tomasz Motyl and Arkadiusz Orzechowski

Int. J. Mol. Sci. 2019, 20(7), 1664; https://doi.org/10.3390/ijms20071664 - 3 Apr 2019

Cited by 20 | Viewed by 5861

Abstract

The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer’s disease (AD) is the most prevalent cause of progressive mental deterioration in aging [...] Read more.

The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer’s disease (AD) is the most prevalent cause of progressive mental deterioration in aging humans, and there is a growing body of evidence that similar disorders (Alzheimer’s-like diseases, ALD) are observed in animals, more than ever found in senescent individuals. This review reveals up to date knowledge in pathogenesis, hallmarks, diagnostic approaches and modalities in AD faced up with ALD related to different animal species. If found at necropsy, there are striking similarities between senile plaques (SP) and neurofibrillary tangles (NFT) in human and animal brains. Also, the set of clinical symptoms in ALD resembles that observed in AD. At molecular and microscopic levels, the human and animal brain histopathology in AD and ALD shows a great resemblance. AD is fatal, and the etiology is still unknown, although the myriad of efforts and techniques were employed in order to decipher the molecular mechanisms of disease onset and its progression. Nowadays, according to an increasing number of cases reported in animals, apparently, biochemistry of AD and ALD has a lot in common. Described observations point to the importance of extensive in vivo models and extensive pre-clinical studies on aging animals as a suitable model for AD disease. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: Amyloid, Extracellular Vesicles and Biomarkers)

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