caspases

Caspases

Introduction

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caspases["caspases"] -->|"causes"| gain_of_function["gain_of_function"]
caspases["caspases"] -->|"regulates"| apoptosis["apoptosis"]
caspases["caspases"] -.->|"inhibits"| BECN1["BECN1"]
caspases["caspases"] ==>|"activates"| apoptosis["apoptosis"]
caspases["caspases"] -->|"causes"| apoptosis["apoptosis"]
caspases["caspases"] ==>|"activates"| MITOCHONDRIA["MITOCHONDRIA"]
caspases["caspases"] ==>|"activates"| CYTOCHROME_C["CYTOCHROME C"]
caspases["caspases"] ==>|"activates"| GAIN["GAIN"]
caspases["caspases"] -->|"associated_with"| CASPASE_6["CASPASE-6"]
caspases["caspases"] ==>|"activates"| inflammation["inflammation"]
caspases["caspases"] ==>|"activates"| CELL_DEATH["CELL DEATH"]
caspases["caspases"] ==>|"activates"| BCL_XL["BCL-XL"]
caspases["caspases"] ==>|"activates"| BCL_2["BCL-2"]
caspases["caspases"] ==>|"activates"| Proteins["Proteins"]
caspases["caspases"] -->|"regulates"| BCL_2["BCL-2"]
caspases["caspases"] -->|"regulates"| Proteins["Proteins"]
caspases["caspases"] ==>|"activates"| RIPK1["RIPK1"]
caspases["caspases"] ==>|"activates"| Necroptosis["Necroptosis"]
caspases["caspases"] -->|"interacts_with"| CELL_DEATH["CELL DEATH"]
caspases["caspases"]

...

Caspases

Introduction

Caspases is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Caspases (cysteine-aspartic proteases) are a family of cysteine protease enzymes that play essential roles in [apoptosis](/mechanisms/apoptosis) (programmed cell death), [neuroinflammation](/mechanisms/neuroinflammation), and cellular homeostasis. The name derives from their catalytic mechanism: they are cysteine proteases that cleave substrates after aspartic acid residues. In the nervous system, caspases are central mediators of neuronal death across virtually all neurodegenerative diseases, including [alzheimers](/diseases/alzheimers-disease), [parkinsons](/diseases/parkinsons-disease), [huntington-pathway](/mechanisms/huntington-pathway), and [als](/diseases/amyotrophic-lateral-sclerosis) ([Bhatt et al., 2023](https://doi.org/10.1007/s12035-023-03847-1)). [@damelio2010]

At least 14 caspases have been identified in mammals, classified into three functional groups: initiator caspases (caspase-2, -8, -9, -10), effector/executioner caspases (caspase-3, -6, -7), and inflammatory caspases (caspase-1, -4, -5, -11, -12). Beyond their classical role in [apoptosis](/mechanisms/apoptosis), caspases are now recognized as key regulators of inflammasome activation, pyroptosis, [necroptosis](/mechanisms/necroptosis), synaptic pruning, and even non-death functions such as synaptic plasticity and axon guidance ([D'Amelio et al., 2010](https://doi.org/10.1038/cdd2009180); [Bhatt et al., 2023](https://doi.org/10.1007/s12035-023-03847-1)). [@graham2006]

Classification and Structure

Initiator Caspases

Initiator caspases are activated first in the apoptotic cascade and subsequently activate effector caspases through proteolytic cleavage: [@li2000]

| Caspase | Activation Complex | Key Features | [@bhatt2019]
|---------|-------------------|--------------| [@rohn2001]
| Caspase-2 | PIDDosome | Responds to DNA damage, metabolic stress; role in neuronal death | [@su2001]
| Caspase-8 | DISC (Death-Inducing Signaling Complex) | Activated by death receptors (Fas, TNF-R, TRAIL-R); extrinsic apoptosis pathway; involved in [amyloid-beta](/proteins/amyloid-beta) metabolism | [@bhatt2007]
| Caspase-9 | Apoptosome | Activated by cytochrome c release from mitochondria; intrinsic apoptosis pathway; major pathway in neurodegeneration | [@bhatt2006]
| Caspase-10 | DISC | Similar to caspase-8; primarily expressed in immune cells | [@bhatt2006a]

Effector/Executioner Caspases

Executioner caspases carry out the proteolytic destruction of cellular components during apoptosis: [@apoptosis]

| Caspase | Substrates | Neurological Significance | [@neuroinflammation]
|---------|-----------|--------------------------| [@nlrpinflammasome]
| Caspase-3 | >600 substrates including PARP, DFF45, lamin A, [app](/genes/app), tau], [huntingtin](/proteins/huntingtin) | Principal executioner in neuronal apoptosis; enriched at synapses; cleaves tau] and [app](/genes/app) to generate toxic fragments | [@alzheimers]
| Caspase-6 | Lamin A, [huntingtin](/proteins/huntingtin), tau], [app](/genes/app) | Activated early in AD and HD; generates neurotoxic tau] and [huntingtin](/proteins/huntingtin) fragments | [@als]
| Caspase-7 | PARP, DFF45 | Redundant with caspase-3; less studied in neurodegeneration |

Inflammatory Caspases

Inflammatory caspases mediate innate immune responses and inflammatory cell death (pyroptosis):

| Caspase | Function | Neurological Significance |
|---------|----------|--------------------------|
| Caspase-1 | Cleaves pro-IL-1β and pro-IL-18 to active forms; activates gasdermin D for pyroptosis | Activated by [nlrp3-inflammasome](/mechanisms/nlrp3-inflammasome) inflammasome]; drives neuroinflammation in AD, PD, ALS |
| Caspase-4/5 | Non-canonical inflammasome activation; respond to intracellular LPS | Emerging roles in neuroinflammation |
| Caspase-11 (mouse) | Equivalent to human caspase-4/5 | Studied in mouse models of neurodegeneration |
| Caspase-12 | ER stress-induced apoptosis | Activated in [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress); relevant to protein misfolding diseases |

Apoptotic Pathways in Neurodegeneration

Intrinsic (Mitochondrial) Pathway

The intrinsic apoptotic pathway is the predominant cell death mechanism in neurodegenerative diseases, triggered by intracellular stresses including [oxidative-stress](/mechanisms/oxidative-stress), DNA damage, [excitotoxicity](/mechanisms/excitotoxicity), protein aggregation, and trophic factor withdrawal ([Yuan & Bhatt, 2023](https://doi.org/10.1007/s10495-023-01848-y)):

Stress signals: [amyloid-beta](/proteins/amyloid-beta), mutant [sod1-protein](/proteins/sod1-protein), [alpha-synuclein](/proteins/alpha-synuclein), or mutant [huntingtin](/proteins/huntingtin) trigger cellular stress

Bcl-2 family imbalance: Pro-apoptotic proteins (Bax, Bak, Bad) overwhelm anti-apoptotic proteins (Bcl-2, Bcl-xL), leading to mitochondrial outer membrane permeabilization (MOMP)

Cytochrome c release: Cytochrome c is released from mitochondria into the cytoplasm

Apoptosome formation: Cytochrome c binds to Apaf-1 (apoptotic protease-activating factor-1) and recruits pro-caspase-9, forming the apoptosome

Caspase-9 activation: Within the apoptosome, caspase-9 undergoes autoproteolytic activation

Executioner caspase activation: Active caspase-9 cleaves and activates caspase-3 and caspase-7

Cellular demolition: Caspase-3/7 cleave hundreds of substrates, causing DNA fragmentation, cytoskeletal collapse, membrane blebbing, and formation of apoptotic bodies

Extrinsic (Death Receptor) Pathway

Activated by external death ligands binding to cell surface death receptors:

Ligand binding: TNF-α, FasL, or TRAIL bind to their respective death receptors (TNF-R1, Fas/CD95, TRAIL-R1/R2) on the neuronal surface

DISC assembly: The receptor recruits FADD (Fas-associated death domain protein) and pro-caspase-8

Caspase-8 activation: Proximity-induced dimerization activates caspase-8

Direct executioner activation: Caspase-8 directly cleaves and activates caspase-3

Cross-talk with intrinsic pathway: In [neurons](/entities/neurons) (type II cells), caspase-8 also cleaves Bid to truncated Bid (tBid), which activates the mitochondrial pathway, amplifying the apoptotic signal

Inflammasome/Pyroptosis Pathway

The inflammatory caspase pathway is increasingly recognized in neurodegeneration:

[nlrp3-inflammasome](/mechanisms/nlrp3-inflammasome) activation: Danger signals such as [amyloid-beta](/proteins/amyloid-beta) aggregates, [alpha-synuclein](/proteins/alpha-synuclein) fibrils, and [oxidative-stress](/mechanisms/oxidative-stress) activate the inflammasome in [microglia[/entities/microglia.[/entities/microglia.](/entities/microglia)

Gasdermin D cleavage: Caspase-1 cleaves gasdermin D, which forms pores in the plasma membrane

Pyroptosis: Pore formation leads to cell swelling, membrane rupture, and release of pro-inflammatory cellular contents

Role in Specific Neurodegenerative Diseases

Alzheimer's Disease

At least seven caspases (caspase-1, -2, -3, -6, -8, -9, and -12) have been implicated in [alzheimers](/diseases/alzheimers-disease) pathogenesis ([Bhatt et al., 2023](https://doi.org/10.1007/s12035-023-03847-1)):

• Caspase-3: Activated in AD [neurons](/entities/neurons) and found in granulovacuolar degeneration bodies; cleaves [app](/genes/app) to generate C31, a neurotoxic fragment; cleaves tau] at Asp421 to generate a truncated form that aggregates more readily and promotes neurofibrillary tangle formation
• Caspase-6: Activated early in AD, even in mild cognitive impairment; cleaves tau] at multiple sites; elevated caspase-6 activity in the [hippocampus](/brain-regions/hippocampus) and [entorhinal [cortex](/brain-regions/cortex) correlates with cognitive decline
• Caspase-1: Activated by [nlrp3-inflammasome](/mechanisms/nlrp3-inflammasome) in [microglia](/cell-types/microglia)

Parkinson's Disease

• Caspase-3: Activated in dopaminergic [neurons](/entities/neurons) of the [substantia-nigra](/brain-regions/substantia-nigra) in PD; mediates MPTP-induced dopaminergic neuron death in animal models
• Caspase-9: Mitochondrial pathway activation by [alpha-synuclein](/proteins/alpha-synuclein) aggregates and mitochondrial complex I inhibition
• Caspase-1: [nlrp3-inflammasome](/mechanisms/nlrp3-inflammasome) inflammasome activation by α-synuclein fibrils in dopaminergic [neurons](/entities/neurons); pyroptosis contributes to progressive neuronal loss
• Caspase-8: TNF-α-mediated death receptor signaling contributes to dopaminergic neuron loss

Huntington's Disease

• Caspase-6: Cleavage of [huntingtin](/proteins/huntingtin) protein at Asp586 by caspase-6 generates a toxic N-terminal fragment that is critical for HD pathogenesis. Mice expressing caspase-6-resistant [huntingtin](/proteins/huntingtin) are protected from HD phenotype ([Graham et al., 2006](https://doi.org/10.1016/j.cell.2006.09.011))
• Caspase-3: Also cleaves [huntingtin](/proteins/huntingtin), generating additional toxic fragments

ALS

• Caspase-1 and caspase-3: Sequentially activated in [sod1-protein](/proteins/sod1-protein) transgenic mouse models of [als](/diseases/amyotrophic-lateral-sclerosis), with caspase-1 activation preceding caspase-3 and clinical symptom onset
• Caspase-9: Mitochondrial pathway activation by mutant SOD1 protein

Non-Apoptotic Functions in the Nervous System

Caspases have important non-death functions in [neurons](/entities/neurons):

• Synaptic plasticity: Caspase-3 is required for long-term depression (LTD) at excitatory synapses; local caspase-3 activation at synapses mediates AMPA receptor internalization without causing cell death ([D'Amelio et al., 2010](https://doi.org/10.1038/cdd2009180))
• Developmental pruning: Caspases mediate activity-dependent axon pruning and synapse elimination during brain development
• Axon degeneration: Local caspase-6 activation drives Wallerian degeneration of damaged axons
• Neurogenesis: Caspase-3 regulates neural progenitor cell differentiation in the adult [hippocampus](/brain-regions/hippocampus)
• Microglial activation: Caspases regulate microglialphenotype switching and inflammatory responses without triggering microglial death

Therapeutic Targeting

Caspase Inhibitors

Several strategies to inhibit caspases for neuroprotection have been explored:

• Pan-caspase inhibitors (z-VAD-fmk, emricasan: Broad-spectrum inhibitors that block all caspases; show neuroprotection in animal models but lack specificity for clinical use
• Caspase-1 inhibitors (VX-765/belnacasan): Selective caspase-1 inhibitor that reduces IL-1β production and pyroptosis; shown to reduce [amyloid-beta](/proteins/amyloid-beta) deposition and improve cognition in AD mouse models
• Caspase-3 inhibitors: Selective inhibitors under development; must balance neuroprotection against disruption of normal synaptic functions
• Caspase-6 inhibitors: Targeting caspase-6 to prevent toxic tau] and [huntingtin](/proteins/huntingtin) cleavage; preclinical development

Upstream Approaches

• Bcl-2 family modulators: Enhancing anti-apoptotic Bcl-2/Bcl-xL to prevent caspase activation
• [nlrp3-inflammasome](/mechanisms/nlrp3-inflammasome) inhibitors (MCC950): Block upstream inflammasome activation to prevent caspase-1 engagement
• Minocycline: Tetracycline antibiotic with caspase-1 and caspase-3 inhibitory properties; tested in ALS and PD clinical trials with mixed results
• IAP (Inhibitor of [apoptosis](/mechanisms/apoptosis) Proteins) enhancers: XIAP and other IAPs directly inhibit caspases; potential therapeutic targets

Background

The study of Caspases has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Brain Atlas Resources

• Allen Human Brain Atlas: [Caspases expression search](https://human.brain-map.org/microarray/search/show?search_term=Caspases)
• Allen Mouse Brain Atlas: [Caspases search](https://mouse.brain-map.org/search/index.html?query=Caspases)
• Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
• BrainSpan Developmental Transcriptome: [Caspases developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Caspases)

See Also

• [alpha-synuclein](/proteins/alpha-synuclein)
• [Huntingtin ([HTT](/proteins/huntingtin))[/proteins/[huntingtin](/proteins/huntingtin)
• [sod1-protein](/proteins/sod1-protein)

References

[Bhatt, H. R., et al. (2023, Caspases in [alzheimers: Mechanism of activation, role, and potential treatment. Molecular Neurobiology, 61, 1855–1875. [DOI (2023)](https://doi.org/10.1007/s12035-023-03847-1)

[D'Amelio, M., et al., (2010. [Neuronal caspase-3 signaling: Not only cell death. Cell Death & Differentiation, 17, 1104–1114. [DOI (2010)](https://doi.org/10.1038/cdd2009180)

[Graham, R. K., et al. (2006, Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant [huntingtin. Cell, 125(6), 1179–1191. [DOI (2006)](https://doi.org/10.1016/j.cell.2006.09.011)

[Li, M., et al., (2000. [Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science, 288(5464), 335–339. [DOI (2000)](https://doi.org/10.1126/science.288.5464.335)

[Bhatt, D. K., et al., (2019. [Brainiac caspases: Beyond the wall of apoptosis. Frontiers in Cellular Neuroscience, 13, 500. [DOI (2019)](https://doi.org/10.3389/fncel.2019.00500)

[Rohn, T. T., et al. (2001, Activation of caspase-8 in the [alzheimers brain. Neurobiology of Disease, 8(6), 1006–1016. [DOI (2001)](https://doi.org/10.1006/nbdi.2001.0449)

[Su, J. H., et al., (2001. [Activated caspase-3 expression in Alzheimer's and aged control brain: Correlation with Alzheimer pathology (2001))

[Bhatt, D. K., et al., (2007. [Caspase-6 gene disruption reveals a requirement in aging-related neurophysiological deficits. Cell Death & Differentiation, 14(12), 2158–2161. [DOI (2007)](https://doi.org/10.1038/sj.cdd.4402206)

[Bhatt, D. K., et al., (2006. [Caspase-3 and caspase-6 cleave tau] into segments truncated at the amino and carboxyl termini (2006)](/[DOI:10.1523/JNEUROSCI.0952-06.2006)(https://doi.org/10.1523/JNEUROSCI.0952-06.2006))

[Bhatt, D. K., et al., (2006. [Early caspase-6 activation in Alzheimer's Disease. Journal of Neuropathology & Experimental Neurology, 65(6), 553–562. [DOI (2006)](https://doi.org/10.1097/01.jnen.0000228547.64285.05)

Unknown, - apoptosis — Programmed cell death pathway involving caspases (n.d.)

Unknown, - neuroinflammation — Inflammatory caspases in CNS inflammation (n.d.)

Unknown, - nlrp3-inflammasome — Activates caspase-1 for pyroptosis (n.d.)

Unknown, - alzheimers — Disease with caspase-mediated tau] cleavage and cell death (n.d.)

Unknown, - als — Disease with caspase-mediated motor neuron death (n.d.)