Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer’s Disease Brain

Vincent, Inez; Jicha, Gregory A.; Rosado, Michelle; Dickson, Dennis W.

doi:10.1523/jneurosci.17-10-03588.1997

Cited by 420 publications

(364 citation statements)

References 54 publications

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“…The presence of cyclin B (a G 2 cyclin) suggests that the cycle has proceeded into G 2 and that there is a block in the cell cycle at some point before M phase. The nature of this block is unknown, but it has been shown that the cdc2/cyclin B complex is present and active in Alzheimer's disease brain tissue (Vincent et al, 1996(Vincent et al, , 1997. Active cdc2 is a mitosis-promoting This question is of particular interest, given the spatial distribution of the spots of hybridization in our samples.…”

Section: Discussionmentioning

confidence: 94%

“…The loss of neurons during adult life, however, is a pathological process that produces behavioral disorders and potentially the death of the organism. Recently, several laboratories have offered evidence that an attempt by the cell to reenter a mitotic cycle precedes many instances of neuronal death (Smith and Lippa, 1995;Arendt et al, 1996Arendt et al, , 1998aVincent et al, 1996Vincent et al, , 1997Vincent et al, , 1998McShea et al, 1997McShea et al, , 1999Nagy et al, 1997aNagy et al, , 1998Busser et al, 1998;Smith et al, 1999). Together, these studies suggest that the paradoxical association of the generative process of cell division with the degenerative process of cell death is found at all stages of the existence of a neuron.…”

mentioning

confidence: 99%

“…In both Alzheimer's disease (Smith and Lippa, 1995;Arendt et al, 1996Arendt et al, , 1998Vincent et al, 1996Vincent et al, , 1997Vincent et al, , 1998McShea et al, 1997McShea et al, , 1999Nagy et al, 1997aNagy et al, , 1998Busser et al, 1998;Smith et al, 1999) and stroke (Hayashi et al, 2000), cell cycle-related proteins appear in neurons at risk for death. These observations suggest that the same prohibitions against cell division that followed a neuron from the ventricular zone through the developmental process remain in effect until the end of life.…”

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confidence: 99%

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DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

2001

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Alzheimer's disease (AD) is a devastating dementia of late life that is correlated with a region-specific neuronal cell loss. Despite progress in uncovering many of the factors that contribute to the etiology of the disease, the cause of the nerve cell death remains unknown. One promising theory is that the neurons degenerate because they reenter a lethal cell cycle. This theory receives support from immunocytochemical evidence for the reexpression of several cell cycle-related proteins. Direct proof for DNA replication, however, has been lacking. We report here the use of fluorescent in situ hybridization to examine the chromosomal complement of interphase neuronal nuclei in the adult human brain. We demonstrate that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in AD have fully or partially replicated four separate genetic loci on three different chromosomes. Cells in unaffected regions of the AD brain or in the hippocampus of nondemented age-matched controls show no such anomalies. We conclude that the AD neurons complete a nearly full S phase, but because mitosis is not initiated, the cells remain tetraploid. Quantitative analysis indicates that the genetic imbalance persists for many months before the cells die, and we propose that this imbalance is the direct cause of the neuronal loss in Alzheimer's disease. Key words: cell cycle; PCNA; cyclin B; hippocampus; nucleus basalis; FISH (fluorescent in situ hybridization); neurodegenerationThe death of nerve cells during early development is a constructive part of pruning and shaping the emerging nervous system. The loss of neurons during adult life, however, is a pathological process that produces behavioral disorders and potentially the death of the organism. Recently, several laboratories have offered evidence that an attempt by the cell to reenter a mitotic cycle precedes many instances of neuronal death (Smith and Lippa, 1995;Arendt et al., 1996Arendt et al., , 1998aVincent et al., 1996Vincent et al., , 1997Vincent et al., , 1998McShea et al., 1997McShea et al., , 1999Nagy et al., 1997aNagy et al., , 1998Busser et al., 1998;Smith et al., 1999). Together, these studies suggest that the paradoxical association of the generative process of cell division with the degenerative process of cell death is found at all stages of the existence of a neuron. The prohibition against cell division begins at the earliest stages of maturation of a neuron. Hindbrain neurons in mice lacking the retinoblastoma tumor suppressor gene are unable to avoid reentering the cell cycle and die by apoptosis immediately after their emigration from the ventricular zone (Lee et al., 1994). Neuronal cell death later in development has also been linked to ectopic cell cycling. Using mutant models of target-related cell death, Herrup and Busser (1995) showed that target-deprived neurons initiated the synthesis of cell cycle enzymes [cyclin D and proliferating cell nuclear antigen (PCNA)] and incorporated bromodeoxyuridine (BrdU) into high molecular weight DN...

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

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DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

2001

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“…Based on the reported activation of cell-cycle proteins in neurodegenerative diseases such as Alzheimer's disease, 24,[55][56][57][58] we investigated the expression and distribution of G 1 to S phase cell-cycle proteins in human postmortem tissues from ALS and age-matched control cases. The G 1 to S phase cell-cycle transition is necessary for cellcycle progression and regulated by the activation of cyclin/cyclin-dependent kinases that hyperphosphorylate pRb, thus de-repressing the transactivational ability of E2F.…”

Section: Resultsmentioning

confidence: 99%

“…Such alterations have been observed in studies on Alzheimer's disease and SIV-E tissues. 55,57,59 The E2F gene family comprises six members sharing homology in the Rb-binding domains. 39 -41 These E2F isoforms complex with the Rb family of proteins at different and defined periods of the cell cycle controlling gene expression within the G 1 phase.…”

Section: Discussionmentioning

confidence: 99%

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

150

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Amyotrophic lateral sclerosis (ALS) is characterizedby progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease exemplified by neuronal loss in the motor cortex, brainstem, and spinal cord ventral horn. This progressive neurodegeneration results in muscle atrophy, paralysis, and death. Disease onset may occur at any age but is most common between 40 to 70 years of age. The average time interval from diagnosis to mortality is ϳ4 years. 1,2 Familial ALS comprises a fraction (5 to 10%) of ALS cases and is predominantly inherited in an autosomal dominant manner and includes mutations in the SOD1 and the ALS2 genes. [3][4][5][6][7] The etiology of ALS is thought to be multifactorial. Factors believed to participate in motor neuron degeneration include glutamate-mediated excitotoxicity, free radical accumulation because of oxidative stress, increased intracellular calcium, mitochondrial dysfunction, cytoskeletal abnormalities, astrogliosis, and genetic mutations. 8 -13 Neuronal dysfunction because of retrograde degeneration of the presynaptic axons may occur as the result of insufficient release of activity-dependent target-derived neurotrophic factors. 14 One important consequence of inappropriate trophic factor support is altered intracellular signaling to the nucleus. Signaling from the cell surface to the nucleus modulates chromatin structure and the activity of transcription factors, resulting in altered gene transcription. One potential mechanism leading to neuronal death in ALS includes altered expression of pro-and anti-apoptotic genes. 15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into...

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