Caspase-Mediated Proteolytic Activation of Calcineurin in Thapsigargin-Mediated Apoptosis in SH-SY5Y Neuroblastoma Cells

Mukerjee, Neeta; McGinnis, Kim M.; Park, Yang Hae; Gnegy, Margaret E.; Wang, Kevin

doi:10.1006/abbi.2000.1889

Cited by 44 publications

(29 citation statements)

References 41 publications

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“…Previous studies have shown that caspase-3 activity is increased by NMDAR activation, and that caspase-3 knockout mice display impaired hippocampal LTD but normal LTP (Li et al, 2010). Furthermore, it was shown that p25/Cdk5 increases caspase-3 activity (Cruz et al, 2003), and activated caspase-3 induces proteolytic cleavage of calcineurin, thereby increasing its catalytic activity (Mukerjee et al, 2000). In the AD mouse brain, increased caspase-3 activity leads to dephosphorylation of GluA1 Ser845 through the activation of calcineurin (D'Amelio et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment

Seo

Giusti‐Rodríguez

Zhou

et al. 2014

Cell

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SUMMARY Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology.

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Section: Discussionmentioning

confidence: 99%

Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment

Seo

Giusti‐Rodríguez

Zhou

et al. 2014

Cell

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“…As calcineurin is required for Aβ-mediated synaptic removal of AMPAR, leading to loss of dendritic spines 29 , and calcineurin A (CN-A) is known to be proteolytically activated by caspase-3 30 , we hypothesized that hippocampal CN-A activity would increase upon caspase-3 cleavage thus inducing GluR1 removal from the PSD. To test whether CN-A is a hippocampal caspase-3 substrate, we performed an immunoblot analysis of the total homogenate from Tg2576 slices treated with z-DEVD-fmk or the vehicle control by using an antibody specific to the N-terminal of CN-A.…”

Section: Caspase-3 Mediates Glur1 Removal From Post-synaptic Sitesmentioning

confidence: 99%

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2010

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SummarySynaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's Disease; yet, the molecular mechanisms underlying synaptic failure are unknown. Here we report a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines, and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's Disease. We show that, in spines, caspase-3 activates calcineurin which, in turn, triggers dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from post-synaptic sites. These molecular modifications lead to alterations of glutamatergic synaptic transmission and plasticity, and correlate with spine degeneration and a deficit in hippocampal-dependent memory. Importantly, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescues the observed Alzheimerlike phenotypes. Therefore, we identify a novel caspase-3-dependent mechanism driving synaptic failure and contributing to cognitive dysfunction in Alzheimer's Disease. These findings point to caspase-3 as possible avenues for pharmacological therapy during early disease stages.Episodic hippocampal-dependent memory loss, the earliest clinical sign of Alzheimer's disease, is thought to be due to changes in synaptic function rather than neuronal loss 1,2 . Specifically, functional brain imaging studies revealed hippocampal mild abnormalities prior to clinical diagnosis and in the absence of structural brain atrophy, suggesting an altered functional connectivity of hippocampus at early stages of disease [3][4][5] .Dendritic spines are likely to be the first affected synaptic elements during early cognitive decline 6 . This is supported by several lines of evidence, such as: i) hippocampal spine-mediated plasticity underlies learning and memory 7 ; ii) post-mortem hippocampus from Alzheimer patients shows a significant decrease in dendritic spine density compared to age-matched controls 8 and iii) transgenic 3 mice expressing mutated forms of the amyloid precursor protein (APP), associated with familial Alzheimer's Disease, show age-dependent reductions in spine density, prior to plaque deposition 9 .Nevertheless, the molecular link between APP mutations triggering Alzheimer's Disease, and the occurrence of early spine loss remains elusive. Interestingly, a localized caspase-3 activity, causing synaptic failure, has been observed in vitro 10 , but the molecular mechanism linking caspase-3 activity to synaptic loss is far from being elucidated.Here, we analyzed caspase-3 activity in hippocampal synapses of the Tg2576 transgenic mouse model, harboring the human APPswe mutant allele linked to familial Alzheimer's Disease 11 . These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is r...

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“…Calcineurin regulates ion channels and cytoskeletal proteins [45,46], inhibits synaptic function [47] and is proteolytically activated by caspase-3 [48]. Akt is an antiapoptotic and progrowth kinase that phosphorylates and inhibits glycogen synthase kinase (GSK) 3b activity, which is required for induction of LTD [49,50].…”

Section: Localized Apoptosis and 'Synapse Involution'mentioning

confidence: 99%

Long-term depression: a cell biological view

Sheng¹,

Ertürk²

2014

Phil. Trans. R. Soc. B

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Recent studies of the molecular mechanisms of long-term depression (LTD) suggest a crucial role for the signalling pathways of apoptosis (programmed cell death) in the weakening and elimination of synapses and dendritic spines. With this backdrop, we suggest that LTD can be considered as the electrophysiological aspect of a larger cell biological programme of synapse involution, which uses localized apoptotic mechanisms to sculpt synapses and circuits without causing cell death.

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Caspase-Mediated Proteolytic Activation of Calcineurin in Thapsigargin-Mediated Apoptosis in SH-SY5Y Neuroblastoma Cells

Cited by 44 publications

References 41 publications

Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment

Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Long-term depression: a cell biological view

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