The Question of Cell Cycle Reentry by Mature Neurons in Response to Amyloid-β and Tau Pathology

2009 ◽  
Vol 17 (1) ◽  
pp. 49-51
Author(s):  
Zixu Mao
Keyword(s):  
Cell Cycle ◽  
Amyloid Β ◽  
Tau Pathology ◽  
Cell Cycle Reentry ◽  
Mature Neurons

Abstract 2357: Src Kinase Inhibition Blocks Thrombin-induced Brain Injuries without Cognitive Side Effects

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Da-Zhi Liu ◽  
Bradley P Ander ◽  
Ali Izadi ◽  
Ken Van ◽  
Xinhua Zhan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cognitive Deficits ◽  
Neuronal Cell ◽  
Thrombin Injection ◽  
Cell Cycle Reentry ◽  
Cell Cycle Inhibition ◽  
Mature Neurons ◽  
Cognitive Side Effects

Intracerebral hemorrhage (ICH) activates thrombin, a potent mitogen. Thrombin triggers mitosis by modulating several intracellular mitogenic molecules including Src family kinases. These molecules regulate mitogen-activated protein kinases (MAPKs) and cell cycle proteins such as cyclin-dependent kinases (Cdks); and play critical roles in mitogenic signaling pathways and cell cycle progression. Since aberrant cell cycle reentry results in death of mature neurons, cell cycle inhibition appears to be a candidate strategy for the treatment of neurological diseases including ICH. However, this can also block cell cycle (proliferation) of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits. We hypothesized that inhibition of cell cycle by blocking mitogenic signaling molecules (i.e., Src family kinase members) blocks cell cycle reentry of mature neurons without injuring NPCs, which will avoid cognitive side effects during cell cycle inhibition treatment for ICH. Our data shows: (1) Thrombin 30U/ml results in apoptosis of mature neurons via neuronal cell cycle reentry in vitro ; (2) PP2 (Src family kinase inhibitor) 0.3 µM attenuates the thrombin-induced neuronal apoptosis via blocking neuronal cell cycle reentry, but does not affect the viability of NPCs at the same doses in vitro ; (3) Intracerebral ventricular thrombin injection (20U, i.c.v.) results in neuron loss in hippocampus and cognitive deficits 5 weeks after thrombin injection in vivo ; (4) PP2 (1mg/kg, i.p.), given immediately after thrombin injection (i.c.v.), blocks the thrombin-induced neuron loss in hippocampus and cognitive deficits, whereas PP2 on its own at the same doses does not affect normal cognition in vivo . These suggest that Src kinase inhibition prevents hippocampal neuron death via blocking neuronal cell cycle reentry after ICH, but does not affect survival of NPCs.

scholarly journals Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity

2021 ◽  
Vol 118 (12) ◽  
pp. e2011876118
Author(s):  
Stefania Ippati ◽  
Yuanyuan Deng ◽  
Julia van der Hoven ◽  
Celine Heu ◽  
Annika van Hummel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dynamic Process ◽  
Cell Cycle Control ◽  
Amyloid Β ◽  
Current View ◽  
Cell Cycle Reentry ◽  
Reporter Signal ◽  
Control Protein ◽  
Cycle Indicator

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.

Activation of Cell Cycle Proteins in Transgenic Mice in Response to Neuronal Loss but not Amyloid-β and Tau Pathology

2009 ◽  
Vol 16 (3) ◽  
pp. 541-549 ◽  
Author(s):  
Joao P. Lopes ◽  
Mathew Blurton-Jones ◽  
Tritia R. Yamasaki ◽  
Paula Agostinho ◽  
Frank M. LaFerla
Keyword(s):  
Cell Cycle ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Tau Pathology ◽  
Cell Cycle Proteins

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals Interactions Between Genes From Aging Pathways Significantly Influence Risk of Alzheimer’s Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 142-143
Author(s):  
Svetlana Ukraintseva ◽  
Konstantin Arbeev ◽  
Hongzhe Duan ◽  
Igor Akushevich ◽  
Mary Feitosa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Older Adults ◽  
Risk Factor ◽  
Human Aging ◽  
Cell Responses ◽  
Cell Cycle Reentry ◽  
Universal Feature ◽  
Igf I ◽  
Ad Prevention ◽  
Stress Damage

Abstract Age is major risk factor for AD; however, relationships between aging and AD are not well understood. Decline in physiological resilience is universal feature of human aging that may also play role in AD. Aging-related pathways (such as IGF-I/P53/mTOR-mediated) that are involved in tissue resilience work in concert to decide outcomes of cell responses to stress/damage, such as survival, apoptosis, autophagy, etc. We hypothesized that interplay among genes in these pathways may influence AD risk as result of epistasis (GxG). We estimated effects of pairwise epistasis between SNPs in 53 genes from respective pathways on AD risk in the LLFS compared with other data (HRS, CHS, LOADFS). We found significant (fdr<0.05) GxG effects on AD risk in older adults across datasets. The SNP rs11765954 in CDK6 gene was involved in top GxG effects on AD in all datasets, when paired with SNPs in BCL2 and PPARGC1A. The CDK6 role in AD could be pleiotropic, depending on its activity in neurons: CDK6 expression is needed for DNA repair and neuronal survival; however, CDK6 overexpression may lead to the cell cycle reentry in postmitotic neurons resulting in apoptosis, which may contribute to neurodegeneration. CDK6 was earlier found to interfere with BCL2 effects on apoptosis, and with PPARGC1A effects on energy metabolism, which might contribute to observed GxG between these genes. We conclude that interactions among genes from biologically connected aging pathways may significantly influence AD risk. Uncovering such GxG effects has a potential to yield new genetic targets for AD prevention/treatment.

scholarly journals Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice

2007 ◽  
Vol 171 (6) ◽  
pp. 2012-2020 ◽  
Author(s):  
Tristan Bolmont ◽  
Florence Clavaguera ◽  
Melanie Meyer-Luehmann ◽  
Martin C. Herzig ◽  
Rebecca Radde ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Β ◽  
Brain Extract ◽  
Tau Pathology ◽  
Intracerebral Infusion

Abstract 4830: The Effects of Stem Cells on C-Kit Up-Regulation and Cell-Cycle Reentry of Neonatal Cardiomyocytes are Mediated by IGF-1 Receptor Activation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xi-Yong Yu ◽  
Yong-Jian Geng ◽  
Xiao-Hong Li ◽  
Chun-Yu Deng ◽  
Shu-Guang Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Fold Increase ◽  
Pi3 Kinase ◽  
Myocardial Regeneration ◽  
Akt Kinase ◽  
Paracrine Effects ◽  
Neonatal Cardiomyocytes ◽  
Cell Cycle Reentry ◽  
Secreted Factors

Mesenchymal stem cells (MSCs) contribute myocardial regeneration, and the beneficial effects may be mediated by paracrine factors produced by MSCs. C-kit positive neonatal cardiomyocytes (NCMs) contribute to myocardial regeneration, but they do not give a robust regenerative response since low expression of c-kit. Cell-cycle reentry of NCMs and insulin-like growth factor (IGF-1) improve myocardial function in infarcted hearts. MSCs and NCMs were prepared from Lewis rats, and cocultured in two chambers which allowed the diffusion of secreted factors from upper chamber to lower chamber, but prevented cell contacts. MSCs secreted significant amount of IGF-1 (159.6 ± 34.4 pg/ug DNA at 24 h, 285.3 ± 28.5 pg/ug DNA at 48 h, and 358.3 ± 39.9 pg/ug DNA at 72 h), whereas the amount of IGF-1 in conditioned medium from NCMs was undetectable assessed by IGF-1 ELISA. Using flow cytometry, we found that the secreted factors by MSCs increased c-kit protein expression, which was attenuated by IGF-1 receptor neutralizing antibody (IGF-1R Ab) and phosphatidylinositol 3 (PI3) kinase inhibitor LY 294002 (NCM vs MSC/NCM vs MSC/NCM+IGF-1R Ab vs MSC/NCM+ LY294002= 1.5 ± 0.6 % vs 5.5 ± 0.3 % vs 1.9 ± 0.6% vs 2.1 ± 0.5%) assessed by flow cytometry. The cytokinesis of NCMs was increased when cocultured with MSC analyzed by calcein fluorescence intensity (3.1 ± 0.5 fold increase, p<0.02). As determined by BrdU assay, the DNA synthesis of NCMs was significantly increased when cocultured with MSC compared to NCM alone (1.8 ± 0.3 fold increase at 48 h, 2.6 ± 0.2 fold increae at 72 h), which was attenuated by IGF-1R Ab and by PI3 kinase inhibitor. To confirm the paracrine effects of MSCs are mediated by IGF-1 signaling and PI3/Akt pathway, we performed in vitro Akt kinase assay using GSK-3 fusion protein as substrate, and found that co-culture system increased the activity of Akt kinase in NCMs, and the IGF-1R Ab and PI3 kinase inhibitor dose-dependent blocked the ability of co-culture system to increase Akt kinase activity. Our results demonstrate that the paracrine effects of MSC on c-kit up-regulation and cell-cycle reentry of NCM are mediated by IGF-1R activation through PI3 kinase/Akt - mediated pathway. These findings provide a new paradigm for the biological effects of IGF-1 on myocardial regeneration. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).

scholarly journals Hypoxia-induced myocardial regeneration

2017 ◽  
Vol 123 (6) ◽  
pp. 1676-1681 ◽  
Author(s):  
Wataru Kimura ◽  
Yuji Nakada ◽  
Hesham A. Sadek
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Systolic Heart Failure ◽  
Cardiac Regeneration ◽  
Oxygen Metabolism ◽  
Functional Improvement ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Cell Cycle Reentry ◽  
And Oxidative Stress

The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration.

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