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Schematic imaging of pathways and factors transforming dopaminergic cells into their senescent forms in aging and/or neurodegeneration (ND). Blue fragment is the DA-producing areas (SN and VTA) in the brain (open boxes mark factors functioning inside these areas); red boxes mark areas where cells are transformed into their senescent forms; orange boxes mark the main critical factors involved in the cell senescence (the boxes, overlapping the blue-yellow border, mark the factors usable on each side). The details of the senescence pathways functioning are described in the text. SC: Senescent cells; DA-Q: dopamine-quinone; DOPAL-Q: 3,4-dihydroxyphenylacetaldehyde-quinone; DDR: damage DNA response; Aβ: amyloid-beta; MAO-B: monoamine oxidase B; NM: neuromelanin; mETC: mitochondrial electron transport chain; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; SN: substantia nigra; VTA: ventral tegmental area.
Context in source publication
Context 1
... conclusion, we are hypothesizing that the interactions between SC and DAS have to be involved in mechanisms of both aging and initiation of neurodegenerative pathologies, in particular, PD and AD (see Figure 1). The role of SC in these mechanisms is associated with specificity of the affected brain area(s) and/or the metabolic pathways chain(s). This suggestion allows the substitution of the conventional symptomatic therapy of the neurodegenerative disorders by approaches that could target their intimate mechanisms. Thus, the results of studies of SC generation and SC spatio-temporal distribution in the cerebral DAS could be a breakthrough in the development of novel pharmaco- logical approaches in the control of aging and neurodegeneration. ...
Citations
... A similar phenomenon was observed in WT 5xFAD (C57BL/6) littermates [24]. The age-related expansion of microglia into the dopamine-producing areas is directed to increase dopamine neuron surveillance by compensating for the progressive decline in morphological complexity (senescence) of microglia [42,43]. Thus, an association of senescent cells, brain plasticity and impairments in cognition might be an attractive target for further studies of interrelations between mechanisms of aging and AD [44]. ...
Unlabelled:
Evident similarities in pathological features in aging and Alzheimer's disease (AD) raise the question of a role for natural age-related adaptive mechanisms in the prevention/elimination of disturbances in interrelations between different brain areas. In our previous electroencephalogram (EEG) studies on 5xFAD- and FUS-transgenic mice, as models of AD and amyotrophic lateral sclerosis (ALS), this suggestion was indirectly confirmed. In the current study, age-related changes in direct EEG synchrony/coherence between the brain structures were evaluated.
Methods:
In 5xFAD mice of 6-, 9-, 12-, and 18-month ages and their wild-type (WT5xFAD) littermates, we analyzed baseline EEG coherence between the cortex, hippocampus/putamen, ventral tegmental area, and substantia nigra. Additionally, EEG coherence between the cortex and putamen was analyzed in 2- and 5-month-old FUS mice.
Results:
In the 5xFAD mice, suppressed levels of inter-structural coherence vs. those in WT5xFAD littermates were observed at ages of 6, 9, and 12 months. In 18-month-old 5xFAD mice, only the hippocampus ventral tegmental area coherence was significantly reduced. In 2-month-old FUS vs. WTFUS mice, the cortex-putamen coherence suppression, dominated in the right hemisphere, was observed. In 5-month-old mice, EEG coherence was maximal in both groups.
Conclusion:
Neurodegenerative pathologies are accompanied by the significant attenuation of intracerebral EEG coherence. Our data are supportive for the involvement of age-related adaptive mechanisms in intracerebral disturbances produced by neurodegeneration.
... However, the AD-associated sensitization of DA receptors was ineffective for further corrections of neuronal network activity in older Tg vs. nTg mice (see Figure 3E,F). The source of the age-dependent changes in the compensatory capability of systemic adaptive mechanisms might be associated, in particular, with the development of senescent processes in the brain [42] that need to be analyzed in further studies. ...
Aging and Alzheimer’s disease (AD) are characterized by common pathological features associated with alterations in neuronal connections. These inevitably affect the functioning of specific brain areas and their interrelations, leading to questions about neuronal plasticity and the compensatory mechanisms associated with dopaminergic (DA) mediation. In this study on twelve-month-old freely moving 5XFAD-transgenic mice, serving as a model of AD, and their wild-type (WT) littermates, we analyze electroencephalograms (EEGs) from the motor cortex (MC), putamen (Pt) and the DA-producing ventral tegmental area (VTA) and substantia nigra (SN). Baseline EEGs in the transgenic mice were characterized by delta 2 activity enhancements in VTA and alpha attenuation in VTA and SN. In contrast to WT mice, which lack differences in EEG from these brain areas, 5XFAD mice showed theta–alpha attenuation and delta 2 and beta 2 enhancements in EEG from both VTA and SN vs. MC. In 5XFAD mice, a DA mimetic, apomorphine, lowered (vs. saline) the theta oscillations in Pt, VTA and SN and enhanced alpha in MC, Pt, VTA and beta 1 in all brain areas. These results and those obtained earlier in younger (six-month-old) mice suggest that the age-related characteristics of cerebral adaptive mechanisms affected by AD might be associated with modification of dopaminergic mediation in the mechanisms of intracerebral dynamic interrelations between different brain areas.
... It seems that, neuromelanin, a DA autoxidation endpoint metabolite may also exert neuroprotective and antioxidative effect by eliminating free Fe 2+ . Subsequently, the neuromelinin damage in the course of PD may cause premature ageing due to accumulation of ASN and excessive ROS, followed by neuroinflammation and reduction of neurogenesis (Nekrasov et al., 2018). Thus it is suggested that disturbances in protective mechanisms and accumulation of L-dopa and DA oxidation products may play a role in the development of PD (Herrera et al., 2017). ...
Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.
... In this respect, discovery of a link between these mechanisms and genetic variants might be one of effective and perspective approaches for understanding of molecular pathways involved in early stages of diseases [33]. The similarity in spectral profiles of EEG interrelations between M1 and Pt, which was observed at the late stage in both nTg and Tg mice (Fig. 4B, D), seems to be linked with the age-dependent DA receptor sensitization provoked by depletion of DA-producing cell population [34][35][36]. Comparable levels of beta prevalence in EEG from M1 and Pt in older Tg versus nTg mice (c.f., Fig. 2B and D and Fig. 3B and D, grey bars) are supportive of this suggestion. Thus, the revelation of genetic aberrations associated with age-dependent receptor sensitization could fill the gap between the early and late stages of neurodegenerative pathologies. ...
Background:
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum.
Objective:
To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression.
Methods:
We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1-359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline.
Results:
In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice.
Conclusion:
We suggest that revealed EEG modifications in ΔFUS(1-359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.
... Another source of the formation and spread of SC in the brain may be the destruction of the substantia nigra, which can be observed mainly in PD, as well as in other neurodegenerative diseases (Nekrasov and Vorobyov, 2018). Hydrogen sulfide has been shown to increase GSH level (Kimura and Kimura, 2004), which plays an important protective role in neuroprotective effects on PD and prevents the destruction of dopaminergic neurons and substantia nigra. ...
Hydrogen sulfide (H2S) is one of the biologically active gases (gasotransmitters), which plays an important role in various physiological processes and aging. Its production in the course of methionine and cysteine catabolism and its degradation are finely balanced, and impairment of H2S homeostasis is associated with various pathologies. Despite the strong geroprotective action of exogenous H2S in C. elegans, there are controversial effects of hydrogen sulfide and its donors on longevity in other models, as well as on stress resistance, age-related pathologies and aging processes, including regulation of senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Here we discuss that the translation potential of H2S as a geroprotective compound is influenced by a multiplicity of its molecular targets, pleiotropic biological effects, and the overlapping ranges of toxic and beneficial doses. We also consider the challenges of the targeted delivery of H2S at the required dose. Along with this, the complexity of determining the natural levels of H2S in animal and human organs and their ambiguous correlations with longevity are reviewed.
... Dopamine (DA) is one of the major neurotransmitters in the brain, playing a key role in brain aging and neurodegenerative diseases, particularly, Parkinson's disease [22]. In PC12 neuronal cells, it was reported that DA pre-treatment at a noncytotoxic concentration may serve as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1, exerting neuroprotective effects [23]. ...
... In the functionalized HyA hydrogels, HPA is used to aid both the attachment of incorporated cells as well as the attachment of the scaffold to the site so that the scaffold is less likely to become detached after transplantation [29,30]. DA, on the other hand, has been used to treat Parkinson's disease patients or to reduce the death of dopaminergic neurons, such that this hydrogel may function to aid neural viability [22,23]. To combine these three compounds together, the synthesis of HyA-DA-HPA was achieved via a two-step reaction ( figure 1). ...
In this work, a novel enzymatically crosslinked injectable hydrogel comprising hyaluronic acid (HyA), dopamine (DA), and 3-(4-Hydroxyphenyl) propionic acid (HPA) conjugates was successfully developed. To the best of our knowledge, it is the first time that HPA is conjugated to a HyA-based backbone. In situ hydrogelation of HyA-DA-HPA occurred in the presence of hydrogen peroxide (H2O2) as an oxidant and horseradish peroxidase (HRP) as a catalyst. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to characterize the chemical reactions between HyA, DA, and HPA. Gel formation completed between 3 s to 5 min depending on the concentrations of polymer, HRP, and H2O2. Crosslinked HyA-DA-HPA gels acquired storage moduli ranging from ~100 Pa to ~20000 Pa (at f = 2000 rad/s). Biocompatibility of the hydrogels was examined with human mesenchymal stem cells (hMSCs) and human induced pluripotent stem cell-derived neural stem cells. The hydrogels made of 2.0 w/v % HyA-DA-HPA hydrogels, 0.24 U/mL HRP and ≤ 0.5 µmol/mL H2O2 were found biocompatible with hMSCs cultured on and encapsulated within the hydrogels. Since HyA serves as a backbone of the extracellular matrix in the central nervous system (CNS) and DA acquires the ability to restore dopaminergic neurons, use of this injectable HyA-DA-HPA hydrogel for stem cell transplantation is a potential treatment strategy for CNS repair and regeneration.
... It is known that cell cycle arrest can stimulate the transition of cells to a so-called senescent state; moreover, aging is another risk factor for AD (Wei et al., 2016). Senescenceassociated secretory phenotypes, which arise from senescence-associated growth arrest, have different effects on adaptive mechanisms of the brain at different stages of disease progression (Nekrasov and Vorobyov, 2018). A primary limitation of this study is that it is only a simple in vitro cell study, which cannot fully recapitulate the complex body environment. ...
Growth arrest-specific 5 (GAS5) is an anti-oncogene that has been extensively studied in tumors. However, research on GAS5 in the context of nervous system disease is rare at present. This study aimed to investigate the role of the long non-coding RNA GAS5 in rat pheochromocytoma cells (PC12 cells). GAS5-overexpressing lentivirus was transfected into PC12 cells, and expression levels of GAS5 and C-myc were detected by real-time PCR. Ratios of cells in S phase were detected by 5-ethynyl-2′-deoxyuridine. Immunohistochemical staining was used to detect the immunoreactivity of neuron microtubule markers Tuj1, doublecortin, and microtubule-associated protein 2. Apoptosis was detected by flow cytometry, while expression of acetylcholine in cells was detected by western blot assay. We found that GAS5 can promote PC12 cells to differentiate into Tuj1-positive neuron-like cells with longer processes. In addition, cell proliferation and cell cycle were significantly suppressed by GAS5, whereas it had no effect on apoptosis of PC12 cells. Our results indicate that GAS5 could increase the expression of choline acetyltransferase and acetylcholine release. Thus, we speculate that GAS5 is beneficial to the recovery of neurons and the cholinergic nervous system.
... We suggest that this EEG approach might be a useful tool for further studies of the adaptive/compensatory neuronal network remodeling associated with disturbances in the dopaminergic system. Regardless of the sources of these disturbances, in particular, associated with ␣-synuclein involvement [57], they are expected to shift the balance between neurogenesis [58] and senescence [59] towards the later, resulting in the neurodegenerative pathology. ...
Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer's disease (AD). 5xFAD mice, a transgenic model of AD, are characterized by an enhanced level of amyloid-β and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-β transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analyzed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.
... We suggest that this EEG approach might be a useful tool for further studies of the adaptive/compensatory neuronal network remodeling associated with disturbances in the dopaminergic system. Regardless of the sources of these disturbances, in particular, associated with ␣-synuclein involvement [57], they are expected to shift the balance between neurogenesis [58] and senescence [59] towards the later, resulting in the neurodegenerative pathology. ...
In humans, heat shock protein 70 is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during aging. Herein, we investigated the protective effect of sub-chronic intranasal administration of human Hsp70 on the state of neurons in the temporal cortex and areas of the hippocampus of old transgenic (Tg) 5XFAD mice (11-13 months), representing a late-onset model of hereditary Alzheimer's disease. Quantitative analysis of the various neuronal pathologies between the two groups (Tg versus nTg) revealed maximal levels of abnormalities in the brains of aged Tg mice. Importantly, intranasal application of HSP70 had profound beneficial effects on neuron morphology in the temporal cortex and hippocampal regions when applied to the aged Tg mice but not in the case of age-matched, non-transgenic, littermate animals. Furthermore, the effect of HSP70 administration on neurons in the hippocampus and temporal cortex differed characteristically between the groups. Using RNA-Seq, we identified a lot of differentially expressed genes in the hippocampus of old Tg mice compared with those of nTg mice. Most importantly, we observed HSP70-induced upregulation of multiple genes participating in antigen processing and presentation especially the members of major histocompatibility complex (class I and II) in the brains of old 5XFAD Tg animals, suggesting that Hsp70 executes its beneficial role via activation of adaptive immunity. Overall, our data enable to conclude that Hsp70 treatment may be a safe and effective therapeutic application against Alzheimer-type neuropathologies manifested at the late stages of the disease.
... Another source of the formation and spread of SC in the brain may be the destruction of the substantia nigra, which can be observed mainly in PD, as well as in other neurodegenerative diseases (Nekrasov and Vorobyov, 2018). Hydrogen sulfide has been shown to increase GSH level (Kimura and Kimura, 2004), which plays an important protective role in neuroprotective effects on PD and prevents the destruction of dopaminergic neurons and substantia nigra. ...
The expression of D-GADD45 gene involved in DNA reparation in Drosophila melanogaster decreases with age. Overexpression of D-GADD45 in the drosophila nervous system prolongs the median and maximum life span without deterioration of the quality of life parameters (fertility and neuromuscular activity). The life span prolongation effect is due to more effective DNA reparation, as spontaneous level of DNA aberrations in the nerve tissue of larvae with D-GADD45 overexpression is reduced significantly.
