Biomolecules

Research

19 pages, 3915 KiB

Open AccessArticle

Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, IGF-1 Depletion, and Behavioral Deficit following Short Term Bilateral Adrenalectomy in Wistar Rats

by Naserddine Hamadi, Ömür Gülsüm Deniz, Ahlam Said Abi Issa, Azim Ullah Shamsul Islam, Naheed Amir, Saeed Tariq Minhas, Nather Madjid, Fatima Khelifi-Touhami, Süleyman Kaplan and Abdu Adem

Biomolecules 2023, 13(1), 22; https://doi.org/10.3390/biom13010022 - 22 Dec 2022

Viewed by 2089

Abstract

The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model [...] Read more.

The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model is one of the few noninvasive models for studying neurodegeneration. In the present study, using stereological technique and ultrastructural examination, we aimed to investigate the impact of short-term adrenalectomy (2 weeks) on different hippocampal neuronal populations in Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons were investigated by measuring the levels of insulin-like growth factor-1 (IGF-1) and β-nerve growth factor (β-NGF). Moreover, we examined whether the biochemical and histological changes in the hippocampus, after short-term adrenalectomy, have an impact on the cognitive behavior of Wistar rats. Stereological counting in the hippocampus revealed significant neuronal deaths in the dentate gyrus and CA4/CA3, but not in the CA2 and CA1 areas, 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons in the dentate, as well as CA4, and CA3 areas, over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 24 h post adrenalectomy, and lasted over the course of two weeks. However, β-NGF was not affected in rats. Using a passive avoidance task, we found a cognitive deficit in the ADX compared to the SHAM operated rats over time (3, 7, and 14 days). In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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15 pages, 1217 KiB

Open AccessArticle

Alterations in Proteostasis System Components in Peripheral Blood Mononuclear Cells in Parkinson Disease: Focusing on the HSP70 and p62 Levels

by Julia D. Vavilova, Anna A. Boyko, Natalya I. Troyanova, Natalya V. Ponomareva, Vitaly F. Fokin, Ekaterina Y. Fedotova, Maria A. Streltsova, Sofya A. Kust, Maria V. Grechikhina, Olga A. Shustova, Tatyana L. Azhikina, Elena I. Kovalenko and Alexander M. Sapozhnikov

Biomolecules 2022, 12(4), 493; https://doi.org/10.3390/biom12040493 - 24 Mar 2022

Cited by 6 | Viewed by 2883

Abstract

Parkinson disease (PD) is attributed to a proteostasis disorder mediated by α-synuclein accumulating in a specific brain region. PD manifestation is often related to extraneuronal alterations, some of which could be used as diagnostic or prognostic PD biomarkers. In this work, we studied [...] Read more.

Parkinson disease (PD) is attributed to a proteostasis disorder mediated by α-synuclein accumulating in a specific brain region. PD manifestation is often related to extraneuronal alterations, some of which could be used as diagnostic or prognostic PD biomarkers. In this work, we studied the shifts in the expression of proteostasis-associated chaperones of the HSP70 family and autophagy-dependent p62 protein values in the peripheral blood mononuclear cells (PBMC) of mild to moderate PD patients. Although we did not detect any changes in the intracellular HSP70 protein pool in PD patients compared to non-PD controls, an increase in the transcriptional activity of the stress-associated HSPA1A/B and HSPA6 genes was observed in these cells. Basal p62 content was found to be increased in PD patients’ PBMC, similarly to the p62 level in substantia nigra neural cells in PD. Moreover, the spontaneous apoptosis level was increased among PBMC and positively correlated with the p62 intracellular level in the PD group. A combined HSPA6- and p62-based analysis among 26 PD patients and 36 age-matched non-PD controls pointed out the diagnostic significance of these markers, with intermediate sensitivity and high specificity of this combination when observing patients diagnosed with PD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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Review

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17 pages, 700 KiB

Open AccessReview

Diverse and Composite Roles of miRNA in Non-Neuronal Cells and Neuronal Synapses in Alzheimer’s Disease

by Xinrong Li, Shih-Chi Chen and Jacque Pak Kan Ip

Biomolecules 2022, 12(10), 1505; https://doi.org/10.3390/biom12101505 - 17 Oct 2022

Cited by 3 | Viewed by 2724

Abstract

Neurons interact with astrocytes, microglia, and vascular cells. These interactions become unbalanced in disease states, resulting in damage to neurons and synapses, and contributing to cognitive impairment. Importantly, synaptic loss and synaptic dysfunction have been considered for years as a main pathological factor [...] Read more.

Neurons interact with astrocytes, microglia, and vascular cells. These interactions become unbalanced in disease states, resulting in damage to neurons and synapses, and contributing to cognitive impairment. Importantly, synaptic loss and synaptic dysfunction have been considered for years as a main pathological factor of cognitive impairment in Alzheimer’s disease (AD). Recently, miRNAs have emerged as essential regulators of physiological and pathological processes in the brain. Focusing on the role of miRNAs in regulating synaptic functions, as well as different cell types in the brain, offers opportunities for the early prevention, diagnosis, and potential treatment of AD-related cognitive impairment. Here, we review the recent research conducted on miRNAs regulating astrocytes, microglia, cerebrovasculature, and synaptic functions in the context of AD-related cognitive impairment. We also review potential miRNA-related biomarkers and therapeutics, as well as emerging imaging technologies relevant for AD research. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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15 pages, 964 KiB

Open AccessReview

Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

by Evgeniy Svirin, Johannes de Munter, Aleksei Umriukhin, Elisaveta Sheveleva, Allan V. Kalueff, Andrei Svistunov, Sergey Morozov, Susanne Walitza and Tatyana Strekalova

Biomolecules 2022, 12(10), 1434; https://doi.org/10.3390/biom12101434 - 7 Oct 2022

Cited by 6 | Viewed by 2745

Abstract

Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal [...] Read more.

Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal neural development and function. The common precursor of the majority of brain gangliosides, GM3, is formed by the sialylation of lactosylceramide, and four derivatives of its a- and b-series, GM1, GD1a, GD1b and GT1b, constitute 95% of all the brain gangliosides. Impairments in ganglioside metabolism due to genetic abnormalities of GM-synthases are associated with severe neurological disorders. Apart from that, the latest genome-wide association and translational studies suggest a role of genes involved in brain ganglioside synthesis in less pervasive psychiatric disorders. Remarkably, the most recent animal studies showed that abnormal ganglioside functions result in dysregulated neuroinflammation, aberrant myelination and altered insulin receptor signalling. At the same time, these molecular features are well established as accompanying developmental psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). This led us to hypothesize a role of deficient ganglioside function in developmental neuropsychiatric disorders and warrants further gene association clinical studies addressing this question. Here, we critically review the literature to discuss this hypothesis and focus on the recent studies on ST3GAL5-deficient mice. In addition, we elaborate on the therapeutic potential of various anti-inflammatory remedies for treatment of developmental neuropsychiatric conditions related to aberrant ganglioside functions. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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23 pages, 5007 KiB

Open AccessReview

Pathological Features and Neuroinflammatory Mechanisms of SARS-CoV-2 in the Brain and Potential Therapeutic Approaches

by Aisha Sodagar, Rasab Javed, Hira Tahir, Saiful Izwan Abd Razak, Muhammad Shakir, Muhammad Naeem, Abdul Halim Abdul Yusof, Suresh Sagadevan, Abu Hazafa, Jalal Uddin, Ajmal Khan and Ahmed Al-Harrasi

Biomolecules 2022, 12(7), 971; https://doi.org/10.3390/biom12070971 - 11 Jul 2022

Cited by 16 | Viewed by 4602

Abstract

The number of deaths has been increased due to COVID-19 infections and uncertain neurological complications associated with the central nervous system. Post-infections and neurological manifestations in neuronal tissues caused by COVID-19 are still unknown and there is a need to explore how brainstorming [...] Read more.

The number of deaths has been increased due to COVID-19 infections and uncertain neurological complications associated with the central nervous system. Post-infections and neurological manifestations in neuronal tissues caused by COVID-19 are still unknown and there is a need to explore how brainstorming promoted congenital impairment, dementia, and Alzheimer’s disease. SARS-CoV-2 neuro-invasion studies in vivo are still rare, despite the fact that other beta-coronaviruses have shown similar properties. Neural (olfactory or vagal) and hematogenous (crossing the blood–brain barrier) pathways have been hypothesized in light of new evidence showing the existence of SARS-CoV-2 host cell entry receptors into the specific components of human nerve and vascular tissue. Spike proteins are the primary key and structural component of the COVID-19 that promotes the infection into brain cells. Neurological manifestations and serious neurodegeneration occur through the binding of spike proteins to ACE2 receptor. The emerging evidence reported that, due to the high rate in the immediate wake of viral infection, the olfactory bulb, thalamus, and brain stem are intensely infected through a trans-synaptic transfer of the virus. It also instructs the release of chemokines, cytokines, and inflammatory signals immensely to the blood–brain barrier and infects the astrocytes, which causes neuroinflammation and neuron death; and this induction of excessive inflammation and immune response developed in more neurodegeneration complications. The present review revealed the pathophysiological effects, molecular, and cellular mechanisms of possible entry routes into the brain, pathogenicity of autoantibodies and emerging immunotherapies against COVID-19. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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18 pages, 8586 KiB

Open AccessFeature PaperReview

Advances in Visualizing Microglial Cells in Human Central Nervous System Tissue

by Christopher E. G. Uff, Karishma Patel, Charming Yeung and Ping K. Yip

Biomolecules 2022, 12(5), 603; https://doi.org/10.3390/biom12050603 - 19 Apr 2022

Cited by 8 | Viewed by 7055

Abstract

Neuroinflammation has recently been identified as a fundamentally important pathological process in most, if not all, CNS diseases. The main contributor to neuroinflammation is the microglia, which constitute the innate immune response system. Accurate identification of microglia and their reactivity state is therefore [...] Read more.

Neuroinflammation has recently been identified as a fundamentally important pathological process in most, if not all, CNS diseases. The main contributor to neuroinflammation is the microglia, which constitute the innate immune response system. Accurate identification of microglia and their reactivity state is therefore essential to further our understanding of CNS pathophysiology. Many staining techniques have been used to visualise microglia in rodent and human tissue, and immunostaining is currently the most frequently used. Historically, identification of microglia was predominantly based on morphological structure, however, recently there has been a reliance on selective antigen expression, and microglia-specific markers have been identified providing increased certainty that the cells observed are in fact microglia, rather than the similar yet distinct macrophages. To date, the most microglia-specific markers are P2Y12 and TMEM119. However, other microglia-related markers can also be useful for demonstrating activation state, phagocytic state, and for neuroimaging purposes in longitudinal studies. Overall, it is important to be aware of the microglia-selectivity issues of the various stains and immunomarkers used by researchers to distinguish microglia in CNS tissue to avoid misinterpretation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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Other

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10 pages, 1720 KiB

Open AccessBrief Report

Effects of Deferasirox in Alzheimer’s Disease and Tauopathy Animal Models

by Ping Kwan, Amy Ho and Larry Baum

Biomolecules 2022, 12(3), 365; https://doi.org/10.3390/biom12030365 - 25 Feb 2022

Cited by 18 | Viewed by 2131

Abstract

The accumulation of iron may contribute to Alzheimer’s disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients. However, desferrioxamine requires injection, which is inconvenient and may hinder compliance. We therefore tested an oral iron chelator, desferasirox (Exjade), [...] Read more.

The accumulation of iron may contribute to Alzheimer’s disease (AD) and other tauopathies. The iron chelator desferrioxamine slows disease progression in AD patients. However, desferrioxamine requires injection, which is inconvenient and may hinder compliance. We therefore tested an oral iron chelator, desferasirox (Exjade), in transgenic animal models. Tg2576 mice overexpress the mutant human APP protein and produce the Aβ peptide. JNPL3 mice (Tau/Tau) overexpress the mutant human tau protein. Crossing these produced APP/Tau mice, overexpressing both APP and tau. Treating the three models with 1.6 mg deferasirox thrice weekly from age 8 to 14 months did not affect memory as measured by contextual fear conditioning or motor function as measured by rotarod, but tended to decrease hyperphosphorylated tau as measured by AT8 immunohistochemistry and immunoblotting. Deferasirox might act by decreasing iron, which aggregates tau, or directly binding tau to inhibit aggregation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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9 pages, 4169 KiB

Open AccessBrief Report

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice

by Tatyana Strekalova, Ekaterina Veniaminova, Evgeniy Svirin, Ekaterina Kopeikina, Tatyana Veremeyko, Amanda W. Y. Yung, Andrey Proshin, Shawn Zheng Kai Tan, Sharafuddin Khairuddin, Lee Wei Lim, Klaus-Peter Lesch, Susanne Walitza, Daniel C. Anthony and Eugene D. Ponomarev

Biomolecules 2021, 11(12), 1759; https://doi.org/10.3390/biom11121759 - 24 Nov 2021

Cited by 5 | Viewed by 3145

Abstract

A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5 [...] Read more.

A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5^−/−) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5^−/− mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5^−/− mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5^−/− mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5^−/− mice. Together, St3gal5^−/− mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative and Neurological Diseases)

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