Overexpression of Cell Cycle Proteins of Peripheral Lymphocytes in Patients with Alzheimer's Disease

Kim, Hye‐Ran; Kwon, Young Ah; Ahn, Inn Sook; Kim, Sang-Ha; Kim, Seonwoo; Jo, Sangmee Ahn; Kim, Doh Kwan

doi:10.4306/pi.2016.13.1.127

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…It is remarkable to note that evidence of association was based on either genetic studies for TP53, VCP, APP, HTT, and PIN1 54 − 57 or proven molecular mechanisms for COPS5, VCP, APP, GNB2L1, HDAC1, HTT, EP300, and TRIM32 54 , 55 , 57 − 63 or verified protein expression changes for COPS5, HSPA8, FSCN1, PIN1, CDK2, ELAVL1, and TCP1. 56 , 62 , 64 − 68 In addition, some IIHs such as FN1, VCAM1, and CDK2 were reported for a role as biomarkers for disease onset and progression, 66 , 69 , 70 while ESR1, HDAC1, and EP300 were reported for a role as potential therapeutic targets. 60 , 61 , 71 Provided all this, we expect that the remainder of the IIHs (HSP90AB1, STUB1, EGFR, HSP90AA1, PDCD6EP, HSPA4, YWHAZ, MCM7, PML, RPS3, and TUBA1A, for which no link to dementia is established yet) might hold relevance to FTD or dementias and thus should be prioritized in both genetic reassessments as well as cell biology work to explore and validate this possibility.…”

Section: Discussionmentioning

confidence: 99%

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Ferrari¹,

Lovering

Hardy³

et al. 2017

J. Proteome Res.

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The genetic analysis of complex disorders has undoubtedly led to the identification of a wealth of associations between genes and specific traits. However, moving from genetics to biochemistry one gene at a time has, to date, rather proved inefficient and under-powered to comprehensively explain the molecular basis of phenotypes. Here we present a novel approach, weighted protein–protein interaction network analysis (W-PPI-NA), to highlight key functional players within relevant biological processes associated with a given trait. This is exemplified in the current study by applying W-PPI-NA to frontotemporal dementia (FTD): We first built the state of the art FTD protein network (FTD-PN) and then analyzed both its topological and functional features. The FTD-PN resulted from the sum of the individual interactomes built around FTD-spectrum genes, leading to a total of 4198 nodes. Twenty nine of 4198 nodes, called inter-interactome hubs (IIHs), represented those interactors able to bridge over 60% of the individual interactomes. Functional annotation analysis not only reiterated and reinforced previous findings from single genes and gene-coexpression analyses but also indicated a number of novel potential disease related mechanisms, including DNA damage response, gene expression regulation, and cell waste disposal and potential biomarkers or therapeutic targets including EP300. These processes and targets likely represent the functional core impacted in FTD, reflecting the underlying genetic architecture contributing to disease. The approach presented in this study can be applied to other complex traits for which risk-causative genes are known as it provides a promising tool for setting the foundations for collating genomics and wet laboratory data in a bidirectional manner. This is and will be critical to accelerate molecular target prioritization and drug discovery.

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Section: Discussionmentioning

confidence: 99%

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Ferrari¹,

Lovering

Hardy³

et al. 2017

J. Proteome Res.

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“…CCA in the brain has been well demonstrated experimentally in models of TBI [11–15], spinal cord injury [21, 24–29], stroke [30, 31], and Alzheimer’s disease (AD) [32–35]; it has also been reported in clinical AD [36, 37]. Both neurons and glial cells show increased expression after CNS injury, and such changes may persist for weeks to months [8–10].…”

Section: Discussionmentioning

confidence: 99%

Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury

Skovira

Matyas

et al. 2016

J Neuroinflammation

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BackgroundTraumatic brain injury (TBI) patients in military settings can be exposed to prolonged periods of hypobaria (HB) during aeromedical evacuation. Hypobaric exposure, even with supplemental oxygen to prevent hypoxia, worsens outcome after experimental TBI, in part by increasing neuroinflammation. Cell cycle activation (CCA) after TBI has been implicated as a mechanism contributing to both post-traumatic cell death and neuroinflammation. Here, we examined whether hypobaric exposure in rats subjected to TBI increases CCA and microglial activation in the brain, as compared to TBI alone, and to evaluate the ability of a cyclin-dependent kinase (CDK) inhibitor (CR8) to reduce such changes and improve behavioral outcomes.MethodsAdult male Sprague Dawley rats were subjected to fluid percussion-induced injury, and HB exposure was performed at 6 h after TBI. Western blot and immunohistochemistry (IHC) were used to assess cell cycle-related protein expression and inflammation at 1 and 30 days after injury. CR8 was administered intraperitoneally at 3 h post-injury; chronic functional recovery and histological changes were assessed.ResultsPost-traumatic hypobaric exposure increased upregulation of cell cycle-related proteins (cyclin D1, proliferating cell nuclear antigen, and CDK4) and microglial/macrophage activation in the ipsilateral cortex at day 1 post-injury as compared to TBI alone. Increased immunoreactivity of cell cycle proteins, as well as numbers of Iba-1+ and GFAP+ cells in both the ipsilateral cortex and hippocampus were found at day 30 post-injury. TBI/HB significantly increased the numbers of NADPH oxidase 2 (gp91phox) enzyme-expressing cells that were co-localized with Iba-1+. Each of these changes was significantly reduced by the administration of CR8. Unbiased stereological assessment showed significantly decreased numbers of microglia displaying the highly activated phenotype in the ipsilateral cortex of TBI/HB/CR8 rats compared with TBI/HB/Veh rats. Moreover, treatment with this CDK inhibitor also significantly improved spatial and retention memory and reduced lesion volume and hippocampal neuronal cell loss.ConclusionsHB exposure following TBI increases CCA, neuroinflammation, and associated neuronal cell loss. These changes and post-traumatic cognitive deficits are reduced by CDK inhibition; such drugs may therefore serve to protect TBI patients requiring aeromedical evacuation.

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“…Amyloid β was shown to promote mTORC1 signalling and CDK2 mediated tau phosphorylation leading to increased neuronal degeneration [ 149 ]. Further, in a study conducted on lymphocytes from AD patients Kim et al (2016) reported significant to moderate upregulation of CDK2, CDK4, CDK6, cyclin B, and cyclin D cell cycle proteins compared to the samples from normal subjects [ 113 ]. An aberrant colocalization of CDK4 and p16 proteins in AD brains compared to age matched controls has been observed [ 150 ].…”

Section: Dysregulated Cell Cycle In Various Neurodegenerative Disordementioning

confidence: 99%

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

Joseph¹,

Mangani²,

Gupta³

et al. 2020

Aging and disease

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Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.

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Overexpression of Cell Cycle Proteins of Peripheral Lymphocytes in Patients with Alzheimer's Disease

Cited by 15 publications

References 40 publications

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

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