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Ischemic Brain Neurodegeneration

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 40460

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Prof. Dr. Ryszard Pluta

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Department of Pathophysiology, Medical University of Lublin, 20-612 Lublin, Poland
Interests: brain ischemia; brain ischemia versus Alzheimer's disease; neurodegeneration; amyloid; presenilins; tau protein; autophagy; mitophagy; apoptosis; genes
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Special Issue Information

Dear Colleagues,

Brain ischemia is one of the most common forms of neurodegeneration, with a series of pathological processes that occur mainly post-ischemia and gradually spread to various brain structures. Both ischemic stroke in humans and experimental brain ischemia are life-threatening pathological events with the development of Alzheimer’s disease-type dementia. New data indicate that ischemic processes may be involved in the development of Alzheimer's disease and that there is a similarity between ischemic neuropathology and Alzheimer's disease. First, ischemic stroke and Alzheimer’s disease have the same risk factors. Second, the post-ischemic brain generates a unique pattern of neuronal death in the hippocampus with serious general brain atrophy, which is similar to the atrophy noted in Alzheimer’s disease. Third, neuroinflammatory reactions have an important role in the progress of the post-ischemic brain injury and Alzheimer’s disease. Fourth, data suggest that post-ischemic brain injury may induce neuropathology of folding proteins characteristic of Alzheimer's disease such as amyloid and tau protein. It is suggested that Alzheimer’s disease-related proteins, like amyloid and tau protein, and their genes, play a fundamental role in post-ischemic neuronal death and neurodegeneration. It is, therefore, important to better understand the contribution of neuronal death to neurodegeneration, the molecular and cellular mechanisms leading to neuronal death, and to identify natural or unnatural molecules that can prevent this death. Progress in understanding new key processes induced by brain ischemia, like changes in the genotype and phenotype of the Alzheimer’s disease-type, which are not yet fully explained, may help develop strategies for prevention and treatment post-ischemic neurodegeneration.

Prof. Dr. Ryszard Pluta
Guest Editor

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Keywords

Brain ischemia
Stroke
Blood-brain barrier
Neuroinflammation
Necrosis
Apoptosis
Autophagy
Mitophagy
Amyloid
Tau protein
Apolipoproteins
Presenilins
α-synuclein
RAGE
LRP1
Gut microbiota
Dementia
Therapeutics

Published Papers (11 papers)

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Editorial

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6 pages, 237 KiB

Open AccessEditorial

Ischemic Brain Neurodegeneration

by Ryszard Pluta

Int. J. Mol. Sci. 2022, 23(12), 6441; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126441 - 09 Jun 2022

Viewed by 1336

Abstract

Aging is an inevitable phenomenon experienced by animals and humans, and its intensity varies from person to person [...] Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

Research

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12 pages, 1593 KiB

Open AccessArticle

CD163 as a Potential Biomarker of Monocyte Activation in Ischemic Stroke Patients

by Rosaria Greco, Chiara Demartini, Anna Maria Zanaboni, Elena Tumelero, Alessandra Persico, Elisa Candeloro, Andrea Morotti, Diana Amantea and Cristina Tassorelli

Int. J. Mol. Sci. 2021, 22(13), 6712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136712 - 23 Jun 2021

Cited by 13 | Viewed by 2196

Abstract

In ischemic stroke patients, a higher monocyte count is associated with disease severity and worse prognosis. The complex correlation between subset phenotypes and functions underscores the importance of clarifying the role of monocyte subpopulations. We examined the subtype-specific distribution of the CD163+ and CD80+ circulating monocytes and evaluated their association with the inflammatory status in 26 ischemic stroke patients and 16 healthy controls. An increased percentage of CD163+/CD16+ and CD163+/CD14++ events occurred 24 and 48 h after a stroke compared to the controls. CD163+ expression was more pronounced in CD16+ non-classical and intermediate monocytes, as compared to CD14+ classical subtype, 24 h after stroke. Conversely, the percentage of CD80+/CD16+ events was unaffected in patients; meanwhile, the percentage of CD80+/CD14+ events significantly increased only 24 h after stroke. Interleukin (IL)-1beta, TNF-alpha, and IL-4 mRNA levels were higher, while IL-10 mRNA levels were reduced in total monocytes from patients versus controls, at either 24 h or 48 h after stroke. The percentage of CD163+/CD16+ events 24 h after stroke was positively associated with NIHSS score and mRS at admission, suggesting that stroke severity and disability are relevant triggers for CD163+ expression in circulating CD16+ monocytes. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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13 pages, 1072 KiB

Open AccessArticle

Alzheimer’s Disease Associated Presenilin 1 and 2 Genes Dysregulation in Neonatal Lymphocytes Following Perinatal Asphyxia

by Agata Tarkowska, Wanda Furmaga-Jabłońska, Jacek Bogucki, Janusz Kocki and Ryszard Pluta

Int. J. Mol. Sci. 2021, 22(10), 5140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105140 - 13 May 2021

Cited by 6 | Viewed by 1967

Abstract

Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however, little is known about the expression of key genes involved in amyloid production by peripheral cells, such as lymphocytes, during the development of hypoxic-ischemic encephalopathy. We analyzed the gene expression of the amyloid protein precursor, β-secretase, presenilin 1 and 2 and hypoxia-inducible factor 1-α by RT-PCR in the lymphocytes of post-asphyxia and control neonates. In all examined periods after asphyxia, decreased expression of the genes of the amyloid protein precursor, β-secretase and hypoxia-inducible factor 1-α was noted in lymphocytes. Conversely, expression of presenilin 1 and 2 genes decreased on days 1–7 and 8–14 but increased after survival for more than 15 days. We believe that the expression of presenilin genes in lymphocytes could be a potential biomarker to determine the severity of the post-asphyxia neurodegeneration or to identify the underlying factors for brain neurodegeneration and get information about the time they occurred. This appears to be the first worldwide data on the role of the presenilin 1 and 2 genes associated with Alzheimer’s disease in the dysregulation of neonatal lymphocytes after perinatal asphyxia. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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15 pages, 1737 KiB

Open AccessArticle

Methionine Diet Evoked Hyperhomocysteinemia Causes Hippocampal Alterations, Metabolomics Plasma Changes and Behavioral Pattern in Wild Type Rats

by Maria Kovalska, Eva Baranovicova, Dagmar Kalenska, Anna Tomascova, Marian Adamkov, Libusa Kovalska and Jan Lehotsky

Int. J. Mol. Sci. 2021, 22(9), 4961; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094961 - 07 May 2021

Cited by 10 | Viewed by 2384

Abstract

L-methionine, an essential amino acid, plays a critical role in cell physiology. High intake and/or dysregulation in methionine (Met) metabolism results in accumulation of its intermediate(s) or breakdown products in plasma, including homocysteine (Hcy). High level of Hcy in plasma, hyperhomocysteinemia (hHcy), is considered to be an independent risk factor for cerebrovascular diseases, stroke and dementias. To evoke a mild hHcy in adult male Wistar rats we used an enriched Met diet at a dose of 2 g/kg of animal weight/day in duration of 4 weeks. The study contributes to the exploration of the impact of Met enriched diet inducing mild hHcy on nervous tissue by detecting the histo-morphological, metabolomic and behavioural alterations. We found an altered plasma metabolomic profile, modified spatial and learning memory acquisition as well as remarkable histo-morphological changes such as a decrease in neurons’ vitality, alterations in the morphology of neurons in the selective vulnerable hippocampal CA 1 area of animals treated with Met enriched diet. Results of these approaches suggest that the mild hHcy alters plasma metabolome and behavioural and histo-morphological patterns in rats, likely due to the potential Met induced changes in “methylation index” of hippocampal brain area, which eventually aggravates the noxious effect of high methionine intake. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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17 pages, 4286 KiB

Open AccessArticle

Oxidative Stress Underlies the Ischemia/Reperfusion-Induced Internalization and Degradation of AMPA Receptors

by Lindsay M. Achzet, Clara J. Davison, Moira Shea, Isabella Sturgeon and Darrell A. Jackson

Int. J. Mol. Sci. 2021, 22(2), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020717 - 13 Jan 2021

Cited by 18 | Viewed by 3620

Abstract

Stroke is the fifth leading cause of death annually in the United States. Ischemic stroke occurs when a blood vessel supplying the brain is occluded. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death as a result of ischemic/reperfusion injury. AMPA receptors composed of a GluA2 subunit are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 subunit. GluA2 undergoes internalization and is subsequently degraded following ischemia/reperfusion. The subsequent increase in the expression of GluA2-lacking, Ca²⁺-permeable AMPARs results in excitotoxicity and eventually delayed neuronal death. Following ischemia/reperfusion, there is increased production of superoxide radicals. This study describes how the internalization and degradation of GluA1 and GluA2 AMPAR subunits following ischemia/reperfusion is mediated through an oxidative stress signaling cascade. U251-MG cells were transiently transfected with fluorescently tagged GluA1 and GluA2, and different Rab proteins to observe AMPAR endocytic trafficking following oxygen glucose-deprivation/reperfusion (OGD/R), an in vitro model for ischemia/reperfusion. Pretreatment with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a superoxide dismutase mimetic, ameliorated the OGD/R-induced, but not agonist-induced, internalization and degradation of GluA1 and GluA2 AMPAR subunits. Specifically, MnTMPyP prevented the increased colocalization of GluA1 and GluA2 with Rab5, an early endosomal marker, and with Rab7, a late endosomal marker, but did not affect the colocalization of GluA1 with Rab11, a marker for recycling endosomes. These data indicate that oxidative stress may play a vital role in AMPAR-mediated cell death following ischemic/reperfusion injury. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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12 pages, 1894 KiB

Open AccessArticle

Pulsed Electromagnetic Fields Stimulate HIF-1α-Independent VEGF Release in 1321N1 Human Astrocytes Protecting Neuron-like SH-SY5Y Cells from Oxygen-Glucose Deprivation

by Fabrizio Vincenzi, Silvia Pasquini, Stefania Setti, Simona Salati, Ruggero Cadossi, Pier Andrea Borea and Katia Varani

Int. J. Mol. Sci. 2020, 21(21), 8053; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218053 - 28 Oct 2020

Cited by 9 | Viewed by 2658

Abstract

Pulsed electromagnetic fields (PEMFs) are emerging as an innovative, non-invasive therapeutic option in different pathological conditions of the central nervous system, including cerebral ischemia. This study aimed to investigate the mechanism of action of PEMFs in an in vitro model of human astrocytes, which play a key role in the events that occur following ischemia. 1321N1 cells were exposed to PEMFs or hypoxic conditions and the release of relevant neurotrophic and angiogenic factors, such as VEGF, EPO, and TGF-β1, was evaluated by means of ELISA or AlphaLISA assays. The involvement of the transcription factor HIF-1α was studied by using the specific inhibitor chetomin and its expression was measured by flow cytometry. PEMF exposure induced a time-dependent, HIF-1α-independent release of VEGF from 1321N1 cells. Astrocyte conditioned medium derived from PEMF-exposed astrocytes significantly reduced the oxygen-glucose deprivation-induced cell proliferation and viability decrease in the neuron-like cells SH-SY5Y. These findings contribute to our understanding of PEMFs action in neuropathological conditions and further corroborate their therapeutic potential in cerebral ischemia. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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Review

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29 pages, 1739 KiB

Open AccessReview

On the Common Journey of Neural Cells through Ischemic Brain Injury and Alzheimer’s Disease

by Jan Kriska, Zuzana Hermanova, Tomas Knotek, Jana Tureckova and Miroslava Anderova

Int. J. Mol. Sci. 2021, 22(18), 9689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189689 - 07 Sep 2021

Cited by 17 | Viewed by 3149

Abstract

Ischemic brain injury and Alzheimer’s disease (AD) both lead to cell death in the central nervous system (CNS) and thus negatively affect particularly the elderly population. Due to the lack of a definitive cure for brain ischemia and AD, it is advisable to carefully study, compare, and contrast the mechanisms that trigger, and are involved in, both neuropathologies. A deeper understanding of these mechanisms may help ameliorate, or even prevent, the destructive effects of neurodegenerative disorders. In this review, we deal with ischemic damage and AD, with the main emphasis on the common properties of these CNS disorders. Importantly, we discuss the Wnt signaling pathway as a significant factor in the cell fate determination and cell survival in the diseased adult CNS. Finally, we summarize the interesting findings that may improve or complement the current sparse and insufficient treatments for brain ischemia and AD, and we delineate prospective directions in regenerative medicine. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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18 pages, 531 KiB

Open AccessReview

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy

by Timea Forró, Zoltán Bajkó, Adrian Bălașa and Rodica Bălașa

Int. J. Mol. Sci. 2021, 22(11), 5621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115621 - 25 May 2021

Cited by 24 | Viewed by 5781

Abstract

Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in cell-to-cell communication and, thus, is integral in the multicellular crosstalk within the NVU. After a stroke, NVU homeostasis is altered, which induces the release of several potential biomarkers into the blood vessels. The addition of biological data representing all constituents of the NVU to clinical and neuroradiological findings can significantly advance stroke evaluation and prognosis. In this review, we present the current literature regarding the possible beneficial roles of exosomes derived from the components of the NVU and multipotent mesenchymal stem cells in preclinical studies of ischemic stroke. We also discuss the most relevant clinical trials on the diagnostic and prognostic roles of exosomes in stroke patients. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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16 pages, 1341 KiB

Open AccessReview

Participation of Amyloid and Tau Protein in Post-Ischemic Neurodegeneration of the Hippocampus of a Nature Identical to Alzheimer's Disease

by Ryszard Pluta, Liang Ouyang, Sławomir Januszewski, Yang Li and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2021, 22(5), 2460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052460 - 28 Feb 2021

Cited by 22 | Viewed by 3331

Abstract

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer's disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer's disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer's disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer's disease-related proteins and genes will provide the most important therapeutic development goals to date. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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11 pages, 847 KiB

Open AccessReview

The Role of Gut Microbiota in an Ischemic Stroke

by Ryszard Pluta, Sławomir Januszewski and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2021, 22(2), 915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020915 - 18 Jan 2021

Cited by 68 | Viewed by 9242

Abstract

The intestinal microbiome, the largest reservoir of microorganisms in the human body, plays an important role in neurological development and aging as well as in brain disorders such as an ischemic stroke. Increasing knowledge about mediators and triggered pathways has contributed to a better understanding of the interaction between the gut-brain axis and the brain-gut axis. Intestinal bacteria produce neuroactive compounds and can modulate neuronal function, which affects behavior after an ischemic stroke. In addition, intestinal microorganisms affect host metabolism and immune status, which in turn affects the neuronal network in the ischemic brain. Here we discuss the latest results of animal and human research on two-way communication along the gut-brain axis in an ischemic stroke. Moreover, several reports have revealed the impact of an ischemic stroke on gut dysfunction and intestinal dysbiosis, highlighting the delicate play between the brain, intestines and microbiome after this acute brain injury. Despite our growing knowledge of intestinal microflora in shaping brain health, host metabolism, the immune system and disease progression, its therapeutic options in an ischemic stroke have not yet been fully utilized. This review shows the role of the gut microflora-brain axis in an ischemic stroke and assesses the potential role of intestinal microflora in the onset, progression and recovery post-stroke. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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15 pages, 1074 KiB

Open AccessReview

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

by Takayuki Nakagomi, Yasue Tanaka, Nami Nakagomi, Tomohiro Matsuyama and Shinichi Yoshimura

Int. J. Mol. Sci. 2020, 21(17), 6360; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176360 - 02 Sep 2020

Cited by 10 | Viewed by 3468

Abstract

Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke. Full article

(This article belongs to the Special Issue Ischemic Brain Neurodegeneration)

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