Caspases are an integral mediator of programmed cell death during development in the CNS, although experiments using mice deficient in various caspases suggest that there is substantial complexity and redundancy in the apoptotic cascades that ultimately lead to the efficient removal of unnecessary and extra neurons.
Caspase activation can occur as a consequence of either intrinsic or extrinsic signals, and can be expressed in a variety of ways including classical apoptosis or necroptosis in the mature nervous system, which are involved in cell death after acute injury and in slowly progressive neurodegenerative diseases.
Caspases may have a special role in the CNS, such as sculpting the axonal and dendritic processes that refine the nervous system both during development and in the adult brain.
Recent data suggest that localized, restricted activation of caspases, even so-called executioner caspases, is an integral part of normal signalling in mature neuronal circuits and synaptic biology.
Local, non-apoptotic activation of caspases may also occur in neurodegenerative processes, whereby caspase activation leads to cleavage of substrates such as tau, which may then contribute to the formation of classical neuropathological lesions such as neurofibrillary tangles.
Caspases are cysteine proteases that mediate apoptosis, which is a form of regulated cell death that effectively and efficiently removes extra and unnecessary cells during development. In the mature nervous system, caspases are not only involved in mediating cell death but also regulatory events that are important for neural functions, such as axon pruning and synapse elimination, which are necessary to refine mature neuronal circuits. Furthermore, caspases can be reactivated to cause cell death as well as non-lethal changes in neurons during numerous pathological processes. Thus, although a global activation of caspases leads to apoptosis, restricted and localized activation may control normal physiology and pathophysiology in living neurons. This Review explores the multiple roles of caspase activity in neurons.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977).
Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).
Gagliardini, V. et al. Prevention of vertebrate neuronal death by the crmA gene. Science 263, 826–828 (1994). This is the first demonstration of the role of caspases in mediating neuronal cell death.
Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205–219 (2004).
Letai, A. et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183–192 (2002).
Willis, S. N. et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315, 856–859 (2007).
Yi, C. H. & Yuan, J. The Jekyll and Hyde functions of caspases. Dev. Cell 16, 21–34 (2009).
Degterev, A., Boyce, M. & Yuan, J. A decade of caspases. Oncogene 22, 8543–8567 (2003).
Duan, H. & Dixit, V. M. RAIDD is a new 'death' adaptor molecule. Nature 385, 86–89 (1997).
Festjens, N., Cornelis, S., Lamkanfi, M. & Vandenabeele, P. Caspase-containing complexes in the regulation of cell death and inflammation. Biol. Chem. 387, 1005–1016 (2006).
Martinou, J. C. et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13, 1017–1030 (1994).
Veis, D. J., Sorenson, C. M., Shutter, J. R. & Korsmeyer, S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240 (1993).
Gonzalez-Garcia, M. et al. bcl-x is expressed in embryonic and postnatal neural tissues and functions to prevent neuronal cell death. Proc. Natl Acad. Sci. USA 92, 4304–4308 (1995).
Nijhawan, D. et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 17, 1475–1486 (2003).
Pazyra-Murphy, M. F. et al. A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and BCL-w. J. Neurosci. 29, 6700–6709 (2009).
Deckwerth, T. L. et al. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411 (1996).
Kim, W. R. et al. Evidence for the spontaneous production but massive programmed cell death of new neurons in the subcallosal zone of the postnatal mouse brain. Eur. J. Neurosci. 33, 599–611 (2011).
Ren, D. et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330, 1390–1393 (2010).
Deshmukh, M., Kuida, K. & Johnson, E. M. Jr. Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J. Cell Biol. 150, 131–143 (2000).
Morata, G., Shlevkov, E. & Perez-Garijo, A. Mitogenic signaling from apoptotic cells in Drosophila. Dev. Growth Differ. 53, 168–176 (2011).
Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998).
Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998).
Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).
Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).
Pompeiano, M., Blaschke, A. J., Flavell, R. A., Srinivasan, A. & Chun, J. Decreased apoptosis in proliferative and postmitotic regions of the caspase 3-deficient embryonic central nervous system. J. Comp. Neurol. 423, 1–12 (2000).
Arnold, S. E., Hyman, B. T., Van Hoesen, G. W. & Damasio, A. R. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Arch. Gen. Psychiatry 48, 625–632 (1991).
Oppenheim, R. W. et al. Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy. J. Neurosci. 28, 1490–1497 (2008).
Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006).
Honarpour, N. et al. Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1. Neuroscience 106, 263–274 (2001).
Christofferson, D. E. & Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22, 263–268 (2009).
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature Rev. Mol. Cell Biol. 11, 700–714 (2010).
Nikolaev, A., McLaughlin, T., O'Leary, D. D. & Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009).
Kuo, C. T., Zhu, S., Younger, S., Jan, L. Y. & Jan, Y. N. Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron 51, 283–290 (2006).
Williams, D. W., Kondo, S., Krzyzanowska, A., Hiromi, Y. & Truman, J. W. Local caspase activity directs engulfment of dendrites during pruning. Nature Neurosci. 9, 1234–1236 (2006).
Rumpf, S., Lee, S. B., Jan, L. Y. & Jan, Y. N. Neuronal remodeling and apoptosis require VCP-dependent degradation of the apoptosis inhibitor DIAP1. Development 138, 1153–1160 (2011).
Huesmann, G. R. & Clayton, D. F. Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 52, 1061–1072 (2006). This study, using a well-established learning paradigm in the zebra finch, suggested strongly that there is a role for caspase activation in normal neuronal plasticity as well as in apoptic events.
Ohsawa, S. et al. Caspase-9 activation revealed by semaphorin 7A cleavage is independent of apoptosis in the aged olfactory bulb. J. Neurosci. 29, 11385–11392 (2009).
Ohsawa, S. et al. Maturation of the olfactory sensory neurons by Apaf-1/caspase-9-mediated caspase activity. Proc. Natl Acad. Sci. USA 107, 13366–13371 (2010).
Li, Z. et al. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859–871 (2010). This study elegantly demonstrated a crucial role for numerous members of the apoptotic cascade that lead to caspase 3 activation in normal electrophysiologically defined synaptic palsticity, thus supporting a paradigm shift in which non-apoptotic roles for this signalling cascade is extended to the CNS.
Jiao, S. & Li, Z. Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70, 758–772 (2011). This study extends the observatons of reference 39. It further implicates caspase 3 activation in LTP to include pro-apototic members of the BCL-2 family, BAD and BAX, in normal electrophysiologically defined LTD, thus implicating these molecules in synaptic plasticity.
Galban, S. & Duckett, C. S. XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ. 17, 54–60 (2010).
Schile, A. J., Garcia-Fernandez, M. & Steller, H. Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev. 22, 2256–2266 (2008).
Bingol, B. et al. Autophosphorylated CaMKIIα acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567–578 (2010).
Cai, F., Frey, J. U., Sanna, P. P. & Behnisch, T. Protein degradation by the proteasome is required for synaptic tagging and the heterosynaptic stabilization of hippocampal late-phase long-term potentiation. Neuroscience 169, 1520–1526 (2010).
Jiang, X. et al. A role for the ubiquitin–proteasome system in activity-dependent presynaptic silencing. J. Neurosci. 30, 1798–1809 (2010).
Akpan, N. et al. Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J. Neurosci. 31, 8894–8904 (2011).
Al-Jamal, K. T. et al. Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing. Proc. Natl Acad. Sci. USA 108, 10952–10957 (2011).
Plesnila, N. et al. Function of BID — a molecule of the bcl-2 family — in ischemic cell death in the brain. Eur. Surg. Res. 34, 37–41 (2002).
Plesnila, N. et al. BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia. Proc. Natl Acad. Sci. USA 98, 15318–15323 (2001).
Yuan, J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14, 469–477 (2009).
Benchoua, A. et al. Specific caspase pathways are activated in the two stages of cerebral infarction. J. Neurosci. 21, 7127–7134 (2001).
Li, H. et al. Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31, 176–182 (2000).
Manabat, C. et al. Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 34, 207–213 (2003).
Wagner, D. C. et al. Cleaved caspase-3 expression after experimental stroke exhibits different phenotypes and is predominantly non-apoptotic. Brain Res. 1381, 237–242 (2011).
Allen, J. W., Eldadah, B. A., Huang, X., Knoblach, S. M. & Faden, A. I. Multiple caspases are involved in β-amyloid-induced neuronal apoptosis. J. Neurosci. Res. 65, 45–53 (2001).
Ayala-Grosso, C. et al. Caspase-3 cleaved spectrin colocalizes with neurofilament-immunoreactive neurons in Alzheimer's disease. Neuroscience 141, 863–874 (2006).
Chan, S. L., Griffin, W. S. & Mattson, M. P. Evidence for caspase-mediated cleavage of AMPA receptor subunits in neuronal apoptosis and Alzheimer's disease. J. Neurosci. Res. 57, 315–323 (1999).
Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005). This review synthesized emerging data that suggested that plaques, tangles and caspase activation share a common pathway, and in particular that caspase cleavage of tau is involved in the formation of tangles.
Cribbs, D. H., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. Caspase-mediated degeneration in Alzheimer's disease. Am. J. Pathol. 165, 353–355 (2004).
Dickson, D. W. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J. Clin. Invest. 114, 23–27 (2004).
Gastard, M. C., Troncoso, J. C. & Koliatsos, V. E. Caspase activation in the limbic cortex of subjects with early Alzheimer's disease. Ann. Neurol. 54, 393–398 (2003).
Li, S. et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).
Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 14, 837–842 (2008).
Kopeikina, K. J. et al. Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human AD brain. Am. J. Pathol. 179, 2071–2082 (2011).
Quintanilla, R. A., Matthews-Roberson, T. A., Dolan, P. J. & Johnson, G. V. Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease. J. Biol. Chem. 284, 18754–18766 (2009).
Stoothoff, W. et al. Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J. Neurochem. 111, 417–427 (2009).
Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E. M. Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).
Cotman, C. W. Apoptosis decision cascades and neuronal degeneration in Alzheimer's disease. Neurobiol. Aging 19, S29–S32 (1998).
Matsui, T. et al. Coordinated expression of caspase 8, 3 and 7 mRNA in temporal cortex of Alzheimer disease: relationship to formic acid extractable aβ42 levels. J. Neuropathol. Exp. Neurol. 65, 508–515 (2006).
Bredesen, D. E. Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependence. Mol. Neurodegener. 4, 27 (2009).
de Calignon, A. et al. Caspase activation precedes and leads to tangles. Nature 464, 1201–1204 (2010). This study demonstrated that caspases could be activated in neurons without that activation leading to the immediate demise of the neuron. Indeed, instead it seemed that neurofibrillary tangles occur in cells that had detectable cytoplasmic caspase activation. These observations argue that caspase activation can have roles other than in apoptosis in neuronal physiology and pathophysiology.
de Calignon, A., Spires-Jones, T. L., Pitstick, R., Carlson, G. A. & Hyman, B. T. Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol. 68, 757–761 (2009).
Halawani, D. et al. Identification of caspase-6-mediated processing of the valosin containing protein (p97) in Alzheimer's disease: a novel link to dysfunction in ubiquitin proteasome system-mediated protein degradation. J. Neurosci. 30, 6132–6142 (2010).
Albrecht, S. et al. Activation of caspase-6 in aging and mild cognitive impairment. Am. J. Pathol. 170, 1200–1209 (2007).
Guo, H. et al. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am. J. Pathol. 165, 523–531 (2004).
LeBlanc, A., Liu, H., Goodyer, C., Bergeron, C. & Hammond, J. Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease. J. Biol. Chem. 274, 23426–23436 (1999).
D'Amelio, M. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nature Neurosci. 14, 69–76 (2011). This elegant series of studies concluded that soluble Aβ species could activate caspase 3 locally in dendritic spines. This may be an extreme form of the LTD-like phenomenon of normal plasticity.
Hyman, B. T. Caspase activation without apoptosis: insight into Aβ initiation of neurodegeneration. Nature Neurosci. 14, 5–6 (2011).
Reifert, J., Hartung-Cranston, D. & Feinstein, S. C. Amyloid β-mediated cell death of cultured hippocampal neurons reveals extensive tau fragmentation without increased full-length tau phosphorylation. J. Biol. Chem. 286, 20797–20811 (2011).
Eckert, A., Schulz, K. L., Rhein, V. & Gotz, J. Convergence of amyloid-β and tau pathologies on mitochondria in vivo. Mol. Neurobiol. 41, 107–114 (2010).
Leung, E. et al. Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex. Neurobiol. Aging 32, 387–397 (2009).
Marchesi, V. T. Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J. 25, 5–13 (2011).
McLellan, M. E., Kajdasz, S. T., Hyman, B. T. & Bacskai, B. J. In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy. J. Neurosci. 23, 2212–2217 (2003).
Wang, X., Su, B., Perry, G., Smith, M. A. & Zhu, X. Insights into amyloid-β induced mitochondrial dysfunction in Alzheimer disease. Free Rad. Biol. Med. 43, 1569–1573 (2007).
Kuchibhotla, K. V. et al. Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59, 214–225 (2008).
Serrano-Pozo, A. et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease. Am. J. Pathol. 179, 1373–1384 (2011).
Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).
D'Amelio, M., Cavallucci, V. & Cecconi, F. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ. 17, 1104–1114 (2010).
Masliah, E. et al. Synaptic and neuritic alterations during the progression of Alzheimer's disease. Neurosci. Lett. 174, 67–72 (1994).
Ingelsson, M. et al. Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–931 (2004).
Su, J. H. et al. DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia. Exp. Neurol. 163, 9–19 (2000).
Rohn, T. T. & Kokoulina, P. Caspase-cleaved TAR DNA-binding protein-43 in Pick's disease. Int. J. Physiol. Pathophysiol. Pharmacol. 1, 25–32 (2009).
Bilsland, J. et al. Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons. J. Neurosci. 22, 2637–2649 (2002).
Leyva, M. J. et al. Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models. Chem. Biol. 17, 1189–1200 (2010).
Graham, R. K. et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191 (2006).
Majumder, P., Chattopadhyay, B., Mazumder, A., Das, P. & Bhattacharyya, N. P. Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. Neurobiol. Dis. 22, 242–256 (2006).
Yamaguchi, Y. et al. Live imaging of apoptosis in a novel transgenic mouse highlights its role in neural tube closure. J. Cell Biol. 195, 1047–1060 (2011).
Florentin, A. & Arama, E. Caspase levels and execution efficiencies determine the apoptotic potential of the cell. J. Cell Biol. 196, 513–527 (2012).
Bateup, H. S. & Sabatini, B. L. For synapses, it's depression not death. Cell 141, 750–752 (2010).
The authors declare no competing financial interests.
A form of regulated cell death that is controlled by the members of the caspase family and BCL-2 family of proteins.
- Programmed cell death
Cell death that is regulated by genetically encoded mechanisms.
- BCL-2 homology domains
Protein–protein interacting domains found in the members of the BCL-2 family of proteins. The members of the BCL-2 family share one or more of the four BH domains (BH1, BH2, BH3 and BH4) that mediate the interactions among different members of the BCL-2 family.
- Caspase recruitment domain
(CARD). A protein–protein interacting motif frequently found in proteins associated with apoptosis and inflammation.
- Death effector domain
(DED). A protein–protein interacting motif found in proteins that mediate caspase activation and apoptosis.
- Death-inducing signalling complex
(DISC). Intracellular signalling complexes associated with the receptors in the tumour necrosis receptor 1 superfamily that are involved in mediating cell death.
A type of developmental abnormality whereby the brain may protrude outside the skull.
A necrotic cell death mechanism regulated by the RIP1 and RIP3 kinases.
- Long-term depression
(LTD). An electrophysiological paradigm that changes synaptic strength following specific electrical or chemical stimuli. It is widely thought to be a model of neuronal plasticity of relevance in learning and memory.
Terminal deoxynucleotidyl transferase dUTP nick end labelling. A method for detecting DNA fragmentation by labelling the terminal end of nucleic acids found in apoptotic cells.
Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone. A cell-permeable, peptide-based pan-caspase inhibitor that irreversibly binds to the catalytic site of caspases and leads to inhibition of apoptosis.
Benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone. A cell-permeable, irreversible peptide-based inhibitor of caspase 3.
A small RNA-associated protein in which mutations and intracellular inclusions are associated with neurodegenerative phenotypes. Hyperphosphorylated and ubiquitinylated neuronal inclusions are found in ubiquitin-positive, tau-negative forms of frontotemporal dementia and in some cases of amyotrophic lateral sclerosis.
About this article
Cite this article
Hyman, B., Yuan, J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 13, 395–406 (2012). https://doi.org/10.1038/nrn3228
Molecular Neurobiology (2022)
Molecular Biology Reports (2021)
Radiation-synthesis of chitosan/poly (acrylic acid) nanogel for improving the antitumor potential of rutin in hepatocellular carcinoma
Drug Delivery and Translational Research (2021)
SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L
Cell Death & Disease (2020)
Nature Reviews Neuroscience (2019)