Differential Expression of Kinases and Cell Cycle Proteins in EW (original) (raw)
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Senescence of the Brain: Focus on Cognitive Kinases
Current Pharmaceutical Design, 2010
Ageing is characterized by alterations in brain anatomy and physiology, finally contributing to an impairment in cognitive functions, such as memory. The most relevant observations indicate that senescent-related cognitive decline is not only due to neuronal loss, instead, functional changes occurring over time play a key role. Overall, these modifications are indeed responsible for an altered interneuronal communication that can represent, rather than morphological modifications, the primum movens leading to cognitive decline. Among the age-induced changes underlying alterations in neuronal communication and synaptic plasticity, those related to neurotransmitter/neurotrophin systems and downstream signalling pathways are of great relevance. In particular, considering that protein kinases play a strategic role aimed to convert the extracellular signals into biological responses, functional alterations on kinases may directly contribute to age-dependent neuronal dysfunctions. Within this context, numerous studies point out on several kinases as positive regulators for memory function and suggest that various memory disturbances are the result of a deficit in kinase signalling pathways. Many kinases associated with synaptic function are indeed age-sensitive; in fact, various studies in senescent animals indicate that a reduction in kinases expression/function in some brain areas correlates with ageing and memory decline. In line with these concepts, pharmacological modulation of kinases may lead to neuroprotective effects that can prevent or counteract age-related memory impairment. This review will mainly focus on the age-induced changes on Protein Kinase C (PKC), Protein Kinase A (PKA), Calcium/calmodulin-dependent Protein Kinase (CaMK), Tyrosine Kinase, widely accepted as key actors in signalling pathways associated with memory.
Review: Cell cycle aberrations and neurodegeneration
Neuropathology and Applied Neurobiology, 2010
The cell cycle is a highly regulated and fundamental cellular process that involves complex feedback regulation of many proteins, and any compromise to its integrity elicits dire consequences for the cell. For example, in neurodegenerative diseases such as Alzheimer disease (AD), evidence for abnormal cell cycle re-entry precedes other hallmarks of disease and as such, implicates cell cycle aberrations in the aetiology of AD. The mechanism(s) for cell cycle re-entry in AD, however, remain unclear. Current theory suggests it to be part of a combination of early events that together elicit the degenerative pathology and cognitive phenotype consistent with the disease. We propose a 'Two-Hit Hypothesis' that highlights the concerted interaction between cell cycle alterations and oxidative stress that combine to produce neurodegeneration. Here, we review the evidence implicating cell cycle mechanisms in AD and how such changes, especially in combination with oxidative stress, would lead to a cascade of events leading to disease. Based on this concept, we propose new opportunities for disease treatment.
Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes
Neurobiology of …, 2000
Neurons of adults apparently lack the components necessary to complete the cell division process. Therefore, in Alzheimer disease, the increased expression of cell cycle-related proteins in degenerating neurons likely leads to an interrupted mitotic process associated with cytoskeletal abnormalities and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer disease, we undertook a study of polo-like kinase (Plk), a protein that plays a crucial role in the cell cycle. Our results show disease-related increases in Plk in susceptible hippocampal and cortical neurons in comparison to young or age-matched controls. An increase in neuronal Plk further implicates aberrations in cell cycle control in the pathogenesis of Alzheimer disease and provides a novel mechanistic basis for therapeutic intervention.
Cycling at the interface between neurodevelopment and neurodegeneration
Cell Death and Differentiation, 2002
The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of
Cell cycle regulatory failure in neurones: causes and consequences
Neurobiology of Aging, 2000
The number of Alzheimer's disease sufferers shows an alarming increase throughout the world. Therefore elucidation of the pathogenic mechanisms leading to Alzheimer's disease and the design of effective treatment, preventive or curative, became imperative. In the last few years several groups have found evidence indicating that the development of Alzheimer-type pathology and the associated excess cell death is the consequence of an aberrant re-entry of neurones into the cell division cycle. We believe that neuronal cell cycle re-entry is followed by regulatory failure that allows neurones to progress into the late stages of the cycle. At this stage, in apoptosis incompetent neurones, the active kinases lead to tau hyperphosphorylation, and the amyloid precursor protein is processed into amyloidogenic fragments. Thus the cell cycle arrest will lead to either the development of Alzheimer's type pathology or to apoptotic neuronal death. Although there are several studies aimed at the elucidation of the precise pathways and mechanisms by which the cell cycle disturbances may lead to Alzheimer's disease there is precious little known about the possible causes of the neuronal cell cycle re-entry. On the other hand we can only speculate on the mechanisms that lead to the subsequent regulatory failure.
International journal of clinical and experimental pathology, 2009
Alterations in cell cycle progression seem to be associated with neuronal death in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). We previously reported disturbances in the control of cell survival/death fate in immortalized lymphocytes from AD patients. These cell cycle dysfunction and impaired apoptosis were considered systemic manifestations of AD disease. The purpose of this study was to evaluate whether these abnormalities are characteristic of AD, or they may be seen in other neurodegenerative disorders such ALS. Our results indicate that alterations in signaling molecules, Akt and ERK1/2, and in the cyclin-dependent kinase complex inhibitors (CDKis) p21(Cip1) and p27(Kip1) are detectable in lymphoblasts from AD patients, but not in ALS patients, suggesting that these variables may be considered for the development of biomarkers of AD. However, lymphocytes from ALS patients do not represent a useful model to study cell cycle-related events associated wit...
Cell cycle and Alzheimer's disease: studies in non-neuronal cells
Journal of Applied Biomedicine, 2010
The most common cause of dementia in the elderly is Alzheimer disease (AD). In Europe, AD is a leading cause of death. The prevalence of this disease in developed countries is increasing because of very significant shifts in life expectance and demographic parameters. AD is characterized by progressive cognitive impairment, resulting from dysfunction and degeneration of neurons in limbic and cortical regions of the brain. Two prominent abnormalities in the affected brain regions are extracellular deposits of β-amyloid, and intracellular aggregates of tau protein in neurofibrillary tangles. The role of these features in AD pathogenesis and progression is not yet completely elucidated. Research over the last decade has revealed that the activation of cell cycle machinery in postmitotic neurons is one of the earliest events in neuronal degeneration in AD. Here we summarized evidences to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Immortalized lymphocytes from AD patients showed an enhanced rate of proliferation associated with G1/S regulatory failure induced by alterations in the cyclin/CDK/pRb/E2F pathway. In addition, these cells have a higher resistance to serum deprivation-induced apoptosis. These neoplastic-like features, cell cycle dysfunction and impaired apoptosis can be considered systemic manifestations of AD disease.
Life, 2021
In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as “senescence”) now is recognized as a complex stress response that culminates with a change in cell ...
Divide and Die: Cell Cycle Events as Triggers of Nerve Cell Death
Journal of Neuroscience, 2004
For over a decade, evidence has mounted that nerve cell death in the CNS is often intimately linked to a process of cell division. Mitotic markers appear in neurons at risk for death in a variety of neurodegenerative conditions, in mouse and in humans. Beyond correlation, studies have shown that experimentally driving the cell cycle in a mature neuron leads to cell death rather than cell division, and blocking cell-cycle initiation can prevent many types of neuronal cell death. This unlikely linkage of cell cycle and cell death pathways is little appreciated among neuroscientists. As only one example, bromodeoxyuridine (BrdU) labeling is often uncritically accepted as proof of neurogenesis when it may well be attributable to a cell cycle-related cell death. This review is meant to enhance appreciation for the relevance of this phenomenon to development and neurodegenerative diseases, in particular the neurodegeneration found in Alzheimer's disease (AD). A brief overview of the participation of mitotic events in human Alzheimer's disease and its mouse models is presented. Against this background, we consider evidence that links various APP (amyloid precursor protein) binding proteins with the cell cycle in Alzheimer's disease. We also examine the role played by oxidative stress as a trigger for cell cycle-related neuronal death. Finally, we discuss the biochemical details of the lethal neuronal cell cycle events and present evidence that non-canonical pathways of DNA replication are probably involved.