ArticleAging cell2022
Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 41 citations in OpenAlex.
- Nα-p-tosyl-L-lysine chloromethyl ketone and Nα-p-tosyl-L-phenylalanine chloromethyl ketone are potent inhibitors of β-amyloid-induced lamin fragmentation.GeroScience · 2026Article
- Association of Cathepsin Proteins with Alzheimer's Disease Risk: An Integrated Observational and Genetic Analysis.Neuromolecular medicine · 2026Observational
- Cathepsins as Core Players in Obesity Pathogenesis: Emerging Therapeutic Targets.Biomolecules · 2026Review
- AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.CNS neuroscience & therapeutics · 2026Article
- Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.Chinese medicine · 2025Review
- Cathepsins in Neurological Diseases.International journal of molecular sciences · 2025Review
- Review
- Hyperactivation of RAB5 disrupts the endosomal Rab cascade leading to endolysosomal dysregulation in Down syndrome: A necessary role for increased APP gene dose.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Role of Glial Cell Senescence in Alzheimer's Disease.Journal of neurochemistry · 2025Review
- Article
- Novel role of curcumin as inhibitor of β-amyloid-induced lamin fragmentation.Histochemistry and cell biology · 2024Article
- Broadening Horizons: Exploring the Cathepsin Family as Therapeutic Targets for Alzheimer's Disease.Aging and disease · 2024Review
- Cathepsin X deficiency alters the processing and localisation of cathepsin L and impairs cleavage of a nuclear cathepsin L substrate.Biological chemistry · 2024Article
- Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.Journal of medicinal chemistry · 2024Article
- Insights into the Multifaceted Roles of Thioredoxin-1 System: Exploring Knockout Murine Models.Biology · 2024Review
- Novel avenues of tau research.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- Article
- Blood Cathepsins on the Risk of Alzheimer's Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study.The journal of prevention of Alzheimer's disease · 2024Observational
- Reevaluating the cause of laminopathy in Alzheimer's disease.Neural regeneration research · 2023Article
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
Abstract
Experimental and clinical therapies in the field of Alzheimer's disease (AD) have focused on elimination of extracellular amyloid beta aggregates or prevention of cytoplasmic neuronal fibrillary tangles formation, yet these approaches have been generally ineffective. Interruption of nuclear lamina integrity, or laminopathy, is a newly identified concept in AD pathophysiology. Unraveling the molecular players in the induction of nuclear lamina damage may lead to identification of new therapies. Here, using 3xTg and APP/PS1 mouse models of AD, and in vitro model of amyloid beta42 (Aβ42) toxicity in primary neuronal cultures and SH-SY5Y neuroblastoma cells, we have uncovered a key role for cathepsin L in the induction of nuclear lamina damage. The applicability of our findings to AD pathophysiology was validated in brain autopsy samples from patients. We report that upregulation of cathepsin L is an important process in the induction of nuclear lamina damage, shown by lamin B1 cleavage, and is associated with epigenetic modifications in AD pathophysiology. More importantly, pharmacological targeting and genetic knock out of cathepsin L mitigated Aβ42 induced lamin B1 degradation and downstream structural and molecular changes. Affirming these findings, overexpression of cathepsin L alone was sufficient to induce lamin B1 cleavage. The proteolytic activity of cathepsin L on lamin B1 was confirmed using mass spectrometry. Our research identifies cathepsin L as a newly identified lamin B1 protease and mediator of laminopathy observed in AD. These results uncover a new aspect in the pathophysiology of AD that can be pharmacologically prevented, raising hope for potential therapeutic interventions.
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