Caspase-3 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization

Li, Zheng; Jo, Jihoon; Jia, Jie–Min; Lo, S.-C.B.; Whitcomb, Daniel J.; Song, Ji‐Hyun; Cho, Kwangwook; Sheng, Morgan

doi:10.1016/j.cell.2010.03.053

Cited by 488 publications

(539 citation statements)

References 62 publications

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“…However, the opinion that caspase-3 is more than just a 'killer' involved in neuronal programmed cell death is supported by studies implicating caspase-3 in regulation of synaptic plasticity [34][35][36] .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…Long-term potentiation (LTP) and long-term depression (LTD) are long-lasting modifications of synapses, in the hippocampus region. Caspase-3 is essential for LTD. 203 During LTD, AMPA receptor in the post-synaptic membrane is internalized and the process is facilitated by caspase-3 and blocked by peptide inhibitors of caspase-3 and -9. It is again worth noting that during LTD, transient caspase-3 activation occurs without causing cell death.…”

Section: Caspases In Neural Developmentmentioning

confidence: 99%

“…Normal synaptic plasticity and function Caspase-3 is important in LTD Caspase-3-mediated internalization of AMPA 203 New functions for old molecules S Shalini et al…”

Section: Conflict Of Interestmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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“…14 Caspase activity is also involved in a longlasting synaptic modification process called long-term depression in NMDA receptor-stimulated hippocampal neurons. 15 Interestingly, NMDA stimulation in cultured cortical neurons caused a fast but low and transient 2 to 3 fold increase in active caspase-3 levels, whereas apoptosis of these neurons was associated with slower but more dramatic, 17 fold increase in the level of active caspase-3. 15 Whereas the mechanisms responsible for these differences in the intensity and dynamics of caspase-3 activation are not clear, they were at least in part attributed to low levels of activation and duration of the proapoptotic BCL-2 family members Bad and Bax.…”

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confidence: 97%

“…15 Interestingly, NMDA stimulation in cultured cortical neurons caused a fast but low and transient 2 to 3 fold increase in active caspase-3 levels, whereas apoptosis of these neurons was associated with slower but more dramatic, 17 fold increase in the level of active caspase-3. 15 Whereas the mechanisms responsible for these differences in the intensity and dynamics of caspase-3 activation are not clear, they were at least in part attributed to low levels of activation and duration of the proapoptotic BCL-2 family members Bad and Bax. 16 Other modes of caspase regulation in CDPs may include tight control over the transcriptional and/or translational levels of caspases and upstream pro-apoptotic regulatory genes, 17,18 post-translational modifications of pro-and anti-apoptotic proteins, 19 and spatiotemporal or level modulation of antiapoptotic genes.…”

mentioning

confidence: 97%