scholarly journals CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease

2018 ◽  
Vol 15 (2) ◽  
pp. 217-231 ◽  
Author(s):  
Fang Huang ◽  
Minghui Wang ◽  
Rong Liu ◽  
Jian-Zhi Wang ◽  
Eric Schadt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Cell Cycle Reentry

scholarly journals Perinuclear Lamin A and Nucleoplasmic Lamin B2 Characterize Two Types of Hippocampal Neurons through Alzheimer’s Disease Progression

2020 ◽  
Vol 21 (5) ◽  
pp. 1841
Author(s):  
Laura Gil ◽  
Sandra A. Niño ◽  
Erika Chi-Ahumada ◽  
Ildelfonso Rodríguez-Leyva ◽  
Carmen Guerrero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Lamin A ◽  
Neuronal Populations ◽  
Cell Cycle Reentry ◽  
Epigenetic Marker ◽  
Age Related ◽  
Elevated Expression

Background. Recent reports point to a nuclear origin of Alzheimer’s disease (AD). Aged postmitotic neurons try to repair their damaged DNA by entering the cell cycle. This aberrant cell cycle re-entry involves chromatin modifications where nuclear Tau and the nuclear lamin are involved. The purpose of this work was to elucidate their participation in the nuclear pathological transformation of neurons at early AD. Methodology. The study was performed in hippocampal paraffin embedded sections of adult, senile, and AD brains at I-VI Braak stages. We analyzed phospho-Tau, lamins A, B1, B2, and C, nucleophosmin (B23) and the epigenetic marker H4K20me3 by immunohistochemistry. Results. Two neuronal populations were found across AD stages, one is characterized by a significant increase of Lamin A expression, reinforced perinuclear Lamin B2, elevated expression of H4K20me3 and nuclear Tau loss, while neurons with nucleoplasmic Lamin B2 constitute a second population. Conclusions. The abnormal cell cycle reentry in early AD implies a fundamental neuronal transformation. This implies the reorganization of the nucleo-cytoskeleton through the expression of the highly regulated Lamin A, heterochromatin repression and building of toxic neuronal tangles. This work demonstrates that nuclear Tau and lamin modifications in hippocampal neurons are crucial events in age-related neurodegeneration.

scholarly journals Regulator of Cell Cycle (RGCC) Expression during the Progression of Alzheimer's Disease

2017 ◽  
Vol 26 (4) ◽  
pp. 693-702 ◽  
Author(s):  
Scott E. Counts ◽  
Elliott J. Mufson
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neuronal Cell ◽  
Cyclin B1 ◽  
Multifunctional Protein ◽  
Protein Levels ◽  
Cell Cycle Reentry ◽  
M Phase

Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD) and may form a basis for selective neuronal vulnerability during disease progression. In this regard, the multifunctional protein regulator of cell cycle (RGCC) has been implicated in driving G1/S and G2/M phase transitions through its interactions with cdc/cyclin-dependent kinase 1 (cdk1) and is induced by p53, which mediates apoptosis in neurons. We tested whether RGCC levels were dysregulated in frontal cortex samples obtained postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), MCI, or AD. RGCC mRNA and protein levels were upregulated by ~50%-60% in MCI and AD compared to NCI, and RGCC protein levels were associated with poorer antemortem global cognitive performance in the subjects examined. To test whether RGCC might regulate neuronal cell cycle reentry and apoptosis, we differentiated neuronotypic PC12 cultures with nerve growth factor (NGF) followed by NGF withdrawal to induce abortive cell cycle activation and cell death. Experimental reduction of RGCC levels increased cell survival and reduced levels of the cdk1 target cyclin B1. RGCC may be a candidate cell cycle target for neuroprotection during the onset of AD.

scholarly journals mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease

2016 ◽  
Vol 13 (2) ◽  
pp. 152-167 ◽  
Author(s):  
Andrés Norambuena ◽  
Horst Wallrabe ◽  
Lloyd McMahon ◽  
Antonia Silva ◽  
Eric Swanson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Neuronal Cell ◽  
Cell Cycle Reentry ◽  
Brain Insulin

scholarly journals Emerging Roles of Inhibitor of Differentiation-1 in Alzheimer’s Disease: Cell Cycle Reentry and Beyond

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1746
Author(s):  
Shang-Der Chen ◽  
Jenq-Lin Yang ◽  
Yi-Chun Lin ◽  
A-Ching Chao ◽  
Ding-I Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Mammalian Cells ◽  
Senile Plaques ◽  
Adult Population ◽  
Cell Cycle Reentry ◽  
Id Proteins ◽  
Underlying Mechanisms

Inhibitor of DNA-binding/differentiation (Id) proteins, a family of helix-loop-helix (HLH) proteins that includes four members of Id1 to Id4 in mammalian cells, are critical for regulating cell growth, differentiation, senescence, cell cycle progression, and increasing angiogenesis and vasculogenesis, as well as accelerating the ability of cell migration. Alzheimer’s disease (AD), the most common neurodegenerative disease in the adult population, manifests the signs of cognitive decline, behavioral changes, and functional impairment. The underlying mechanisms for AD are not well-clarified yet, but the aggregation of amyloid-beta peptides (Aβs), the major components in the senile plaques observed in AD brains, contributes significantly to the disease progression. Emerging evidence reveals that aberrant cell cycle reentry may play a central role in Aβ-induced neuronal demise. Recently, we have shown that several signaling mediators, including Id1, hypoxia-inducible factor-1 (HIF-1), cyclin-dependent kinases-5 (CDK5), and sonic hedgehog (Shh), may contribute to Aβ-induced cell cycle reentry in postmitotic neurons; furthermore, Id1 and CDK5/p25 mutually antagonize the expression/activity of each other. Therefore, Id proteins may potentially have clinical applications in AD. In this review article, we introduce the underlying mechanisms for cell cycle dysregulation in AD and present some examples, including our own studies, to show different aspects of Id1 in terms of cell cycle reentry and other signaling that may be crucial to alter the neuronal fates in this devastating neurodegenerative disease. A thorough understanding of the underlying mechanisms may provide a rationale to make an earlier intervention before the occurrence of cell cycle reentry and subsequent apoptosis in the fully differentiated neurons during the progression of AD or other neurodegenerative diseases.

scholarly journals Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

2014 ◽  
Vol 62 ◽  
pp. 273-285 ◽  
Author(s):  
Kiran Bhaskar ◽  
Nicole Maphis ◽  
Guixiang Xu ◽  
Nicholas H. Varvel ◽  
Olga N. Kokiko-Cochran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Neuronal Cell ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Pathogenic tau disrupts the cellular program that maintains neuronal identity

2021 ◽  
Author(s):  
Adrian Beckmann ◽  
Paulino Ramirez ◽  
Maria Gamez ◽  
William J. Ray ◽  
Bess Frost
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Formation ◽  
Therapeutic Approaches ◽  
Nuclear Pleomorphism ◽  
Mesenchymal Transition ◽  
Neuronal Identity ◽  
Cell Cycle Activation

AbstractNeurons in human Alzheimer’s disease acquire phenotypes that are also present in various cancers, including over-stabilization of the cytoskeleton, nuclear pleomorphism, decondensation of constitutive heterochromatin, and aberrant activation of the cell cycle. Unlike in cancer, in which cell cycle activation drives tumor formation, activation of the cell cycle in post-mitotic neurons is sufficient to induce neuronal death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related “tauopathies.” We have combined network analysis of human Alzheimer’s disease and mouse tauopathy with mechanistic studies in Drosophila to discover that pathogenic forms of tau drive abortive cell cycle activation by disrupting the cellular program that maintains neuronal identity. Mechanistically, we identify Moesin, a prognostic biomarker for cancer and mediator of the epithelial-mesenchymal transition (EMT), as a major effector of tau-induced neurotoxicity. We find that aberrant activation of Moesin in neurons acts through the actin cytoskeleton to dysregulate the cellular program that maintains neuronal identity. Our study identifies mechanistic parallels between tauopathy and cancer and sets the stage for novel therapeutic approaches.

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