ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 106 citations in OpenAlex.
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- Infection of 5xFAD mice with a mouse-adapted SARS-CoV-2 does not alter Alzheimer's disease neuropathology yet induces wide-spread changes in gene expression across diverse cell types.bioRxiv : the preprint server for biology · 2025Article
- Targeting the glymphatic system: Aβ accumulation and phototherapy strategies across different stages of Alzheimer's disease.Translational neurodegeneration · 2025Review
- Calpastatin, a calpain specific inhibitor, reduce seizures in a mouse model of temporal lobe epilepsy.Epilepsia open · 2025Article
- Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.Acta neuropathologica · 2024Review
- Extracellular CIRP Induces Calpain Activation in Neurons via PLC-IPMolecular neurobiology · 2023Article
- Review
- Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17.Cellular and molecular life sciences : CMLS · 2022Article
- Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease.Cell reports · 2020Article
- Intake of ω-6 Polyunsaturated Fatty Acid-Rich Vegetable Oils and Risk of Lifestyle Diseases.Advances in nutrition (Bethesda, Md.) · 2020Review
- Involvement of calpain in the neuropathogenesis of Alzheimer's disease.Medicinal research reviews · 2019Review
- Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo.Autophagy · 2019Article
- LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice.Molecular neurobiology · 2019Article
- Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond.BioMed research international · 2019Review
- Autophagy stimulation as a promising approach in treatment of neurodegenerative diseases.Metabolic brain disease · 2018Review
- Neuronal Cell Death.Physiological reviews · 2018Review
- Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach.Frontiers in neuroinformatics · 2018Article
- Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology.Progress in neurobiology · 2017Review
- Roles of tau protein in health and disease.Acta neuropathologica · 2017Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer's disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.