Calcium‐Activated Neutral Proteinase (Calpain) System in Aging and Alzheimer's Disease<sup>a</sup>

Nixon, Ralph A.; Saitô, Kenichi; Grynspan, Frida; Griffin, W. R.; Katayama, Sadao; Honda, Toshiyuki; Mohan, Panaiyur S.; Shea, Thomas B.; Beermann, Mary Lou

doi:10.1111/j.1749-6632.1994.tb44402.x

Cited by 240 publications

(85 citation statements)

References 110 publications

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“…The levels of these two calpains were very low at DIV5, but they both accumulated from DIV10. This is a rare phenomenon in vitro cell culture conditions, although some in vivo experiments found that µ-calpain and m-calpain were abnormally high in the brains of Alzheimer's disease patients (Nilsson et al, 1990;Nixon et al, 1994). Moreover, in Parkinson's disease, m-calpain is quantitatively upregulated in the substantia nigra and locus coeruleus (MouattPrigent et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, as mentioned above, increased calpain mRNA expression or protein accumulation cannot be effectively reproduced by in vitro neurotoxin treatment using neuron-like cell lines or primary cultures, because the proteolytic activation of calpains involves 'qualitative' regulation not a 'quantitative' change by RNA expression. However, in vivo studies reported high calpain immunoreactivity in many neurodegenerative disorders (the increase of total calpains), and the activation of calpain by cleavage or by autolytic-specific antibodies (the increase of activated calpain), suggesting both 'qualitative' and 'quantitative' regulation (Nilsson et al, 1990;Nixon et al, 1994;Tsuji et al, 1998). Our results demonstrate that primary longterm culture of the cortex itself is a good model system of neurodegeneration and the up-regulation (quantitative) and activation (quantitative) of calpain systems are involved in degeneration of primary neuronal culture.…”

Section: Discussionmentioning

confidence: 99%

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Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Kim

Oh²,

Park³

et al. 2007

Exp Mol Med

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Primary neuronal culture is a powerful tool to study neuronal development, aging, and degeneration. However, cultured neurons show signs of cell death after 2 or 3 weeks. Although the mechanism underlying this phenomenon has not been elucidated, several preventive methods have been identified. Here we show that the neuronal loss in primary cortical culture involves calpain activation and subsequent neuronal cell death. Neuronal loss during cultivation showed destruction of neurites and synapses, and a decrease in neuron numbers. µ-Calpain and m-calpain were initially activated and accumulated by increased RNA expression. This neuronal death exhibited neurodegenerative features, such as conversion of p35 to p25, which is important in the developmental process and in the pathogenesis of Alzheimer's disease. But, postnatal and aged rat cortex did not show calpain activation and prolonged processing of p35 to p25, in contrast to the long-term culture of cortical neurons. In addition, the inhibition of calpains by ALLM or ALLN blocked the conversion of p35 to p25, indicating that the calpain activity is essential for the neurodegenerative features of cell death. Taken together, this study shows that the neuronal loss in primary cortical cultures involves neurodegeneration-like cell death through the activation of calpains and the subsequent processing of p35 to p25, but not developmental apoptosis or aging. Our results suggest that the long term primary culture of cortical neurons represent a valuable model of neurodegeneration, such as Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Kim

Oh²,

Park³

et al. 2007

Exp Mol Med

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“…In addition, the cytosolic localization of PrP may be involved in the pathogenesis of prion disease (26). Thus, calpain activation in tandem with caspase activation leads to apoptosis since a combination of caspase and calpain inhibitors is necessary to inhibit prion protein-mediated apoptosis (50). Furthermore, it seems that calpain may play a role in removing cytosolic prion protein (79).…”

Section: Calpain Activation In Other Pathological Conditionsmentioning

confidence: 99%

Involvement of Calpain Activation in Neurodegenerative Processes

et al. 2006

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One of the challenges in the coming years will be to better understand the mechanisms of neuronal cell death with the objective of developing adequate drugs for the treatment of neurodegenerative disorders. Caspases and calpains are among the best-characterized cysteine proteases activated in brain disorders. Likewise, during the last decade, extensive research revealed that the deregulation of calpains activity is a key cytotoxic event in a variety of neurodegenerative disorders. Moreover, interest in the role of calpain in neurodegenerative processes is growing due to implication of the involvement of cdk5 in neurodegenerative diseases. Since calpain inhibitors appear to not only protect brain tissue from ischemia, but also to prevent neurotoxicity caused by such neurotoxins as â-amyloid or 3-nitropropionic acid, the currently available data suggest that calpain and cdk5 play a key role in neuronal cell death. It seems clear that the inappropriate activation of cysteine proteases occurs not only during neuronal cell death, but may also contribute to brain pathology in ischemia and traumatic brain disorders. Pharmacological modulation of calpain activation may, therefore, be useful in the treatment of neurodegenerative disorders. It is possible, although difficult, to develop synthetic inhibitors of cysteine proteases, specifically calpains. The inhibition of calpain activation has recently emerged as a potential therapeutic target for the treatment of neurodegenerative diseases. 135

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“…Calpains also potentiate the function of proapoptotic Bcl-2-family members, both via transcription-dependent and transcription-independent pathways, and can act in a positive feedback loop with caspase family members (Blomgren et al, 2001). Previous studies indicate that chronically elevated calpain activity contributes to neurodegeneration in Alzheimer's Disease (Siman, 1992;Saito et al, 1993;Nixon et al, 1994). Moreover, calpain cleavage of NR2B to remove the C-terminal region that is required for maintaining NR2B-type NMDARs in the synapse (Prybylowski et al, 2005) is expected to shift the balance of NMDAR signaling away from survival and toward cell death pathways (Wu et al, 2007;Papadia and Hardingham, 2007).…”

Section: Enhanced Calpain Activity and Striatal Neuronal Vulnerabilitmentioning

confidence: 99%

Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Cowan¹,

Fan²,

Fan³

et al. 2008

J. Neurosci.

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Huntington disease (HD), caused by CAG expansion in the ubiquitously expressed huntingtin gene, is characterized by early dysfunction and death of striatal medium-sized spiny neurons (MSNs). Previous work has shown MSN-specific alterations in NMDA receptor (NMDAR) expression and cell death signaling. Furthermore, studies in HD human brain tissue and a knock-in mouse model demonstrate increases in calpain activity, which can be stimulated by NMDARs and contribute to excitotoxicity. Here, we report increased calpain activity in MSNs from the yeast artificial chromosome (YAC) transgenic mouse model of HD, expressing human full-length huntingtin with 128 polyglutamine repeats (YAC128), compared with wild type. Moreover, the calpain-cleaved product of NMDAR subunit NR2B is increased early, and NR2B expression levels are reduced, in YAC128 striatum. Although steady-state NMDAR surface expression is similar in wild-type and YAC128 MSNs, the rate of loss of NR2B-containing surface receptors is enhanced in YAC128 MSNs, suggesting that NMDAR forward trafficking to the surface is also faster, as previously reported for YAC72 MSNs. Calpain inhibitor-1 treatment normalized the loss rate of surface NMDARs in YAC128 MSNs to that of wild type, and significantly increased surface NMDAR expression in YAC128, but not in wild type or YAC72. With acute NMDAR overstimulation, the increase in calpain activity correlated with polyglutamine length, and calpain inhibitor treatment reduced NMDA-induced apoptosis in YAC72 and YAC128 MSNs to wild-type levels. Thus, the cumulative effect of increasing huntingtin polyglutamine length is to enhance MSN sensitivity to excitotoxicity at least in part by calpain-mediated cell death signaling.

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Calcium‐Activated Neutral Proteinase (Calpain) System in Aging and Alzheimer's Disease^a

Cited by 240 publications

References 110 publications

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Involvement of Calpain Activation in Neurodegenerative Processes

Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

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Calcium‐Activated Neutral Proteinase (Calpain) System in Aging and Alzheimer's Diseasea

Cited by 240 publications

References 110 publications

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Involvement of Calpain Activation in Neurodegenerative Processes

Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

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Calcium‐Activated Neutral Proteinase (Calpain) System in Aging and Alzheimer's Disease^a