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Differentiated neurons display specific biochemical, physiological and
morphological properties that apparently prevent them from further cell
division. Nevertheless, expression of cell cycle modulators persists after
neuronal differentiation and is upregulated under stress conditions, such
as trophic factor deprivation, oxidative stress and the pr...
Context in source publication
Context 1
... cell cycle of eukaryotic cells comprises four main successive phases: G1 phase (first gap), S phase (DNA synthesis), G2 phase (second gap) and M phase (mitosis) (Figure 1). Transition between the different phases and subsequent progression through the mitotic cycle is driven by a group of protein kinases whose activity is central to this process, the cyclin-dependent kinase (CDKs), and requires the binding of their activating partners cyclins, whose levels of expression varies throughout the cycle. ...
Citations
... The previous study assumed that further invective protein accumulation is required for causing the apoptosis of neuron cells [51]. This suggestion was accepted by presenting the stimulation of some mechanisms in the G2 phase, arising the development of NFTs as well as amyloid-β plaques [52] in programmed cell death inept neurons. They cause significant augment phosphorylation of amyloid precursor protein (APP) through the CDK2, CDK4, and CDK5, which rises its β-amyloid making as well as APP breakdown through the stimulated caspases enzymes during the process of cell-cycle [53][54][55]. ...
Globally cancer and Alzheimer's disease (AD) are two major diseases and still, there is no clearly defined molecular mechanism. There is an opposite relation between cancer and AD which are the proportion of emerging cancer was importantly slower in AD patients, whereas slow emerging AD in patients with cancer. In cancer, regulation of cell mechanisms is interrupted by an increase in cell survival and proliferation, while on the contrary, AD is related to augmented neuronal death, that may be either produced by or associated with amyloid-β (Aβ) and tau deposition. Stated that the probability that disruption of mechanisms takes part in the regulation of cell survival/death and might be implicated in both diseases. The mechanism of actions such as DNA-methylation, genetic polymorphisms, or another mechanism of actions that induce alteration in the action of drugs with significant roles in resolving the finding to repair and live or die might take part in the pathogenesis of these two ailments. The functions of miRNA, p53, Pin1, the Wnt signaling pathway, PI3 KINASE/Akt/mTOR signaling pathway GRK2 signaling pathway, and the pathophysiological role of oxidative stress are presented in this review as potential candidates which hypothetically describe inverse relations between cancer and AD. Innovative materials almost mutual mechanisms in the aetiology of cancer and AD advocates novel treatment approaches. Among these treatment strategies, the most promising use treatment such as tyrosine kinase inhibitor, nilotinib, protein kinase C, and bexarotene.
... There have been reports of neuron loss in the hippocampus's subregions, particularly in the DG, which shows significant cell loss in AD patients who have mild cognitive impairment [26][27][28]. Multiple modalities of programmed cell death have been recorded in AD [29][30][31][32]. ...
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aβ25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.
... Among the genes screened, many of them belong to the Wnt signaling pathway, PI3K/Akt signaling pathway, and heparan sulfate proteoglycan binding genes. Abnormalities in these pathways are often associated with neurodegenerative diseases [48][49][50]. TSPAN3, part of the tetraspanin superfamily, features four transmembrane domains and six cysteine residues in the large luminal domain. It is extensively expressed in the nervous system, particularly in neurons and astrocytes [51]. ...
Misfolding and aggregation of α-Synuclein (α-Syn), which are hallmark pathological features of neurodegenerative diseases such as Parkinson’s disease (PD) and dementia with Lewy Bodies, continue to be significant areas of research. Among the diverse forms of α-Syn – monomer, oligomer, and fibril, the oligomer is considered the most toxic. However, the mechanisms governing α-Syn oligomerization are not yet fully understood. In this study, we utilized genome-wide CRISPR/Cas9 loss-of-function screening in human HEK293 cells to identify negative regulators of α-Syn oligomerization. We found that tetraspanin 3 (TSPAN3), a presumptive four-pass transmembrane protein, but not its homolog TSPAN7, significantly modulates α-Syn oligomer levels. TSPAN3 was observed to interact with α-Syn oligomers, regulate the amount of α-Syn oligomers on the cell membrane, and promote their degradation via the clathrin-AP2 mediated endo-lysosome pathway. Our findings highlight TSPAN3 as a potential regulator of α-Syn oligomers, presenting a promising target for future PD prevention and treatment strategies.
... The transformation of a healthy senile brain to AD pathology inaugurates the coexistence of two types of pyramidal neurons. One population expresses nucleoplasmic lamin B2, a sign of active transcription and abortive cell cycle that leads to neuronal death [31,[101][102][103][104], and the population of AD neurons, characterized by an anomalous lamin A expression [28][29][30]105], which stops the cell cycle, thus protecting the nucleus and generating a new cytoskeleton [106][107][108]. Early AD stages are also distinguished by the gradual disappearance of nuclear AT100 [34], which is strongly associated with chromatin disorganization [29]. ...
The dentate gyrus (DG) of the human hippocampus is a complex and dynamic structure harboring mature and immature granular neurons in diverse proliferative states. While most mammals show persistent neurogenesis through adulthood, human neurogenesis is still under debate. We found nuclear alterations in granular cells in autopsied human brains, detected by immuno-histochemistry. These alterations differ from those reported in pyramidal neurons of the hippocam-pal circuit. Aging and early AD chromatin were clearly differentiated by the increased epigenetic markers H3K9me3 (heterochromatin suppressive mark) and H3K4me3 (transcriptional euchroma-tin mark). At early AD stages, lamin B2 was redistributed to the nucleoplasm, indicating cell-cycle reactivation, probably induced by hippocampal nuclear pathology. At intermediate and late AD stages, higher lamin B2 immunopositivity in the perinucleus suggests fewer immature neurons, less neurogenesis, and fewer adaptation resources to environmental factors. In addition, senile samples showed increased nuclear Tau interacting with aged chromatin, likely favoring DNA repair and maintaining genomic stability. However, at late AD stages, the progressive disappearance of phos-phorylated Tau forms in the nucleus, increased chromatin disorganization, and increased nuclear autophagy support a model of biphasic neurogenesis in AD. Therefore, designing therapies to alleviate the neuronal nuclear pathology might be the only pathway to a true rejuvenation of brain circuits.
... Additionally, compared to the age-matched controls AD neurons display elevated levels of other cell-cycle markers, indicating an exit of neurons from the quiescence stage (G 0 ) and re-entry into the cell cycle (Yang et al., 2003;Bonda et al., 2009;Tan et al., 2012). In particular, the cytoplasm of diseased neurons express Cyclin D, CDK-4, and Ki67, and elevation of the Cyclin D/CDK-4 complex in the cells corroborates the fact that these cells have indeed crossed the G 1 phase and are no longer in G 0 [ Fig. 4] (McShea et al., 1997;Nagy et al., 1997;Ueberham, 2003;Heine et al., 2004;Ueberham and Arendt, 2005;Aulia and Tang, 2006;Currais et al., 2009a;van Leeuwen and Hoozemans, 2015). As described in previous sections, EBV has long been known to influence various cyclin/CDK complexes. ...
The Epstein-Barr virus is a well-known cell cycle modulator. To establish successful infection in the host, EBV alters the cell cycle at multiple steps via antigens such as EBNAs, LMPs, and certain other EBV-encoded transcripts. Interestingly, several recent studies have indicated the possibility of EBV's neurotrophic potential. However, the effects and outcomes of EBV infection in the CNS are under-explored. Additionally, more and more epidemiological evidence implicates the cell-cycle dysregulation in neurodegeneration. Numerous hypotheses describe the triggers that force post-mitotic neurons to re-enter the cell cycle are prevalent. Apart from the known genetic and epigenetic factors responsible, several reports have shown the association of microbial infections with neurodegenerative pathology. Although, studies implicating the herpesvirus family members in neurodegeneration exist, the involvement of Epstein-Barr virus (EBV), in particular, is under-evaluated. Interestingly, a few clinical studies have reported patients of AD or PD to be seropositive for EBV. Based on the findings mentioned above, in this review, we propose that EBV infection in neurons could drive it towards neurodegeneration through dysregulation of cell-cycle events and induction of apoptosis.
... Aberrant cell cycle re-entry (CCR) although observed in neuronal populations makes them vulnerable to neurodegenerative disorders, yet a precise molecular mechanism triggering CCR in neurons remains unidentified (Marathe et al., 2015). The possible scenario may be that, in response to SD-induced stress stimuli, neurons are pushed into the cell cycle but the array of proteins required for the cell cycle does not allow its completion; thus, cell is neither able to revert nor complete division, making it non-functional and to undergo apoptosis (Currais et al., 2009). Based on previous reports and current findings in the expression of apoptotic proteins, it may be suggested that aberrant cell cycle activation in neurons induced apoptosis in response to stressful stimuli of acute SD. ...
Sleep deprivation due to present-day lifestyle and late-hours work commitments are associated with a broad spectrum of neurobehavioral complications. Moreover, women, as they age, become prone to the cumulative effects of menopause such as sleep disturbances, adiposity, and inflammation which are attributed to a compromised immuno-neuro-endocrine axis. So far, no effective therapeutic remedy is available to mitigate the adverse effects of SD. The current study was aimed to elucidate the neuroprotective potential of n-Butanol fraction obtained from hydroalcoholic extract of Tinospora cordifolia stem (B-TCE). Four groups of female rats are (1) Vehicle-undisturbed sleep, (2) Vehicle-sleep deprived (between 6 a.m. and 6 p.m.), (3) B-TCE oral feeding for 2 weeks and sleep deprivation, and (4) B-TCE alone undisturbed sleep group. Novel Object Recognition test was used to study cognitive impairments and Rotarod for motor coordination. Rats were then sacrificed to study the expression of various marker proteins in the hippocampus and piriform cortex regions of the brain by western blotting. SD was observed to impair the exploratory behavior and neuromuscular coordination, whereas, B-TCE pre-treatment was observed to ameliorate these behavioral functions’- impairments and further suppressed the changes in the expression of markers for synaptic plasticity, inflammation, cell survival, and apoptosis pathways. The current data suggest that B-TCE may be effective in the management of acute SD-associated impairments in learning and memory functions and neuromuscular coordination.
... As soon as neurons are born, they lose the capacity of division and differentiation. In stress conditions, like oxidative stress and DNA damage, and after neuronal differentiation, cell cycle modulators' expression increased (35). The cell cycle consists of four main phases: G1, S, G2, and M. Neurons remain in a G0 phase. ...
Objective:
Change in astrocytes is one of the first pathological symptoms of Alzheimer's disease (AD). Understanding the signaling pathways in astrocytes can be a great help in treating of AD. This study aimed to investigate signaling pathway relations between low dose of methamphetamine (METH), the apoptosis, cell cycle, and glutamine (Gln) pathways in the activated astrocyte.
Materials and methods:
In this experimental study, the activated astrocyte cells were exposed to a low dose of METH (12.5 μM) which was determined by Thiazolyl blue tetrazolium bromide (MTT) method. The groups were: group 1 cells with Aβ, group 2 cells with METH, group 3 cells with METH after 24 hours of adding Aβ (Aβ+METH, treated group), group 4 cells with Aβ after 24 hours of adding METH (METH+Aβ, prevention group), and group 5 as the control. The Gln was assayed by high-performance liquid chromatography (HPLC), and also the apoptosis, and cell cycle and BAX, BCL-X expression was evaluated.
Results:
The amount of Gln was increased, and the value of late and early apoptosis was reduced in the treatment groups, and necrosis is decreased in the prevention group (group 4 compared to group 1). Moreover, it was revealed through cell cycle analysis that G2 in group 4 was reduced compared to group 1 and the expression of BAX, BAX/ BCL-X, and BCL-X in group 3 and group 4, was decreased and increased, respectively compared to group 1.
Conclusion:
These findings suggest that perhaps a non-toxic dosage of METH (low dose) can reduce the amount of apoptosis and BAX expression and increase the expression of BCL-X. Furthermore, the cells are arrested in the G2 phase and can raise the amount of extracellular glutamine, which has a protective role in neuron cells. These findings may provide a new perspective to design a new drug with less toxic results.
... Similarly, a regulatory role for dopamine over cellular dynamics in postnatal SVZs was reported by Coronas et al. [50]. In contrast, the adult-neurogenesis-mediated reactivation of the neuronal cell cycle is considered a potent mediator of cell death in Alzheimer's disease, indicating the demand for the defined control of cell cycle stimulation in the neurogenic niche, rather than in mature postmitotic neurons [51]. ...
In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.
... The data suggest that depending on the disease stage and a patient's health status, activation of the immune system may be protective or detrimental, or even may significantly contribute to the triggering of AD pathology [2][3][4][5][6][7]. A growing body of evidence indicates that re-activation of cell cycle in mature post-mitotic neurons may be a critical pathogenetic event in AD [8][9][10][11]. Terminally differentiated neurons exist in a quiescent state of the cell cycle; however, several studies have demonstrated that cell cycle-related proteins are expressed in post-mitotic neurons in healthy adult brain [12]. Because the expression of cell-cycle regulators in healthy differentiated neurons is not related to neuronal proliferation, it was suggested that they may have a non-canonical role, possibly linked to neuronal plasticity or stability. ...
In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer’s disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated. Cyclin cD2 was also found to be down-regulated in AD neocortex and hippocampus. Our novel data indicate that Aβ peptide and inflammation both significantly decreased the expression of cD2, suggesting that Aβ peptides may also contribute to downregulation of cD2 in AD brain.
... Among others, these genomic changes may affect molecular (cellular) pathways of genome stability maintenance or protection against CIN (e.g., cell cycle regulation) [36,37]. The ability for neurons to enter erroneously into the cell cycle seems to underlie the formation of aneuploidy and other types of CIN in the diseased (Alzheimer's disease) brain [9,34,35,38,39]. Actually, CIN/aneuploidy confined to affected brain areas has been determined as an important element of the pathogenic cascade in Alzheimer's disease [40,41]. ...
Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.
