In situ evidence for DNA fragmentation in Huntingtonʼs disease striatum and Alzheimerʼs disease temporal lobes

Dragunow, Michael; Faull, Richard L. M.; Lawlor, P.; Beilharz, Erica; Singleton, K.; Walker, Elizabeth; Mee, Edward

doi:10.1097/00001756-199505090-00026

Cited by 317 publications

(127 citation statements)

References 5 publications

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“…The work of Greene and colleagues (Ferrari and Greene, 1994;Farinelli and Greene, 1996;Park et al, 1996) has suggested that cdc2 and other cell-cycle proteins may also participate in apoptosis of differentiated neuronal cells. At least some (Su et al, 1994;Dragunow et al, 1995;Lassmann et al, 1995;Smale et al, 1995), but certainly not all (Migheli et al, 1994; for review, see Dickson et al, 1995), neurons of AD brain exhibit features of apoptotic death. Recently, the mouse homolog (ALG3) of an identified familial AD gene (STM2) encoding for presenilin 2 was shown to rescue T lymphocytes from T cell receptor-and Fas-induced apoptosis (Vito et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1997

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We have shown previously that M-phase phospho-epitopes accumulate in neuronal tau proteins incorporated into the hallmark neurofibrillary tangles (NFT) of Alzheimer's disease (AD). In M phase, the epitopes are produced by cdc2/cyclin B1 kinase by a highly conserved mechanism believed to be quiescent in terminally differentiated neurons of adult brain. To determine whether an M-phase mechanism is possible in AD neurons, we first investigated the presence of cdc2 and cyclin B1 in AD. Both proteins were enriched in neurons with NFT and in neurons susceptible to NFT. An antibody specific for catalytically active cdc2 stained numerous NFT-containing neurons in AD but did not react with normal neurons. Double-labeling studies showed that active cdc2 and cyclin B1 coexist in AD neurons and co-localize with AD-specific mitotic phosphoepitopes. Mitotic kinase purified from AD and normal brain, using the yeast p13suc1 protein as affinity ligand, showed higher histone H1 phosphorylation activity in AD. Accordingly, the levels of cdc2 and cyclin B1 in p13suc1 fractions from AD were higher than normal. Consistent with a physiological relationship between NFT and mitotic kinase, NFT proteins copurified with and became phosphorylated by the p13suc1-bound kinase in vitro. Furthermore, cdc2/cyclin B1 is the only one of several proline-directed kinases that created the TG/MC mitotic phospho-epitopes in recombinant tau in vitro. These findings suggest that aberrantly reexpressed cdc2/cyclin B1 in NFT-bearing neurons in AD brain contributes to the generation of M-phase phospho-epitopes in NFT. Key words: cdc2; cyclin B; p13suc1; neuronal degeneration; Alzheimer's disease; neurofibrillary tangleMarked neuronal loss in Alzheimer's disease (AD) is often preceded by deposition of neurofibrillary tangles (NFT) that contain hyperphosphorylated proteinaceous aggregates called paired helical filaments (PHF) (for review, see Terry et al., 1994) (Trojanowski et al., 1993). Although these lesions have been studied for decades, little is known about the biochemical mechanisms that produce them. We recently presented evidence that certain NFT-specific monoclonal antibodies (i.e., the TG and MC series) recognize phospho-epitopes that are of a mitotic nature, displaying a temporally restricted pattern of appearance during M phase in a variety of proliferating eukaryotic cells (Vincent et al., 1996). We also reported that the conserved M-phase MPM-2 phosphoepitope is abundant in NFT-containing neurons in AD, but is not detected in neurons of normal brain (Vincent et al., 1996). Based on these findings, we hypothesized that a mitotic posttranslational mechanism participates in the formation of NFT and the death of neurons in AD.To gather support for this hypothesis, we first isolated mitotic kinase from brain using the yeast p13suc1 protein as affinity ligand and compared the phosphorylation activity of the kinase from AD brain with that of normal brain. We found that mitotic kinase activity is elevated in AD brain in comparison with normal. We als...

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Section: Discussionmentioning

confidence: 99%

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

et al. 1997

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“…7,8 Ab generated apoptosis in several in vitro models, associated with caspase activation, 9-14 both of which were also documented in AD brains. 15,16 Recent data further evidenced a major role of the transcription factor c-Jun in mediating Ab-induced apoptosis. [17][18][19] Overexpression of this factor was detected in neurons surrounding senile plaques.…”

Section: Introductionmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

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“…This form of cell death appears to be crucial for mammalian development and subsequent tissue homeostasis. Inappropriate apoptosis has been implicated in several neurodegenerative diseases such as Alzheimer's, 1 amyotrophic lateral sclerosis 2 and Huntington's, 1 as well as ischaemic damage 3 and several forms of retinal degeneration collectively referred to as retinitis pigmentosa (RP). 4 ± 6 RP is characterised by an initial loss of night vision followed by a progressive loss of peripheral and central visual acuity.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress induces caspase-independent retinal apoptosis in vitro

2000

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Apoptosis is the mode of cell death in retinitis pigmentosa (RP), a heterogeneous group of retinal degenerations. The activation of the caspase proteases forms a pivotal step in the initiation and execution phase of apoptosis in many cells. Inhibition of caspases has been reported to prevent apoptosis in many model systems. However, we demonstrate the absence of caspase activation during retinal cell apoptosis in vitro which involves phosphatidylserine (PS) externalisation, DNA nicking and cell shrinkage. In addition, zVAD-fmk, DEVD-CHO and BD-fmk, inhibitors of the caspases, were unable to alter the characteristics or kinetics of apoptosis, implying that retinal cell death in vitro follows a caspase-independent pathway. We have previously demonstrated the ability of reactive oxygen species (ROS) to act as mediators of retinal cell apoptosis in vitro as well as the ability of antioxidants to prevent retinal cell apoptosis. Here we demonstrate the oxidative inactivation of caspases in this model of retinal apoptosis and provide evidence for an oxidative stress driven cell death pathway that does not involve caspase activity and which retains key features of apoptotic cell death. Furthermore, our data indicates that apoptotic events such as PS exposure, DNA nicking and cell shrinkage may occur independently of caspase activity. Cell Death and Differentiation (2000) 7, 282 ± 291.

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In situ evidence for DNA fragmentation in Huntingtonʼs disease striatum and Alzheimerʼs disease temporal lobes

Cited by 317 publications

References 5 publications

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

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

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Oxidative stress induces caspase-independent retinal apoptosis in vitro

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