ArticleJournal of Alzheimer's disease : JAD2014
Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic.
Article in Journal of Alzheimer's disease : JAD, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 83 citations in OpenAlex.
- Cystatin C and its Role in the Neuro-Glial-Vascular Unit: Implications for Cerebrovascular Diseases and Neurodegeneration.Neuroscience bulletin · 2026Review
- Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.Cellular and molecular neurobiology · 2026Review
- Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.Current topics in medicinal chemistry · 2026Review
- Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors.Nature chemical biology · 2025Article
- Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease.MedComm · 2025Article
- Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease.ACS chemical biology · 2025Review
- Article
- Activation of Cytosolic Cathepsin B Activity in the Brain by Traumatic Brain Injury and Inhibition by the Neutral pH Selective Inhibitor Probe Z-Arg-Lys-AOMK.ACS chemical neuroscience · 2025Article
- Comprehensive medicinal chemistry survey highlights a portfolio of lead molecules for Alzheimer's disease therapy.Frontiers in chemistry · 2025Review
- mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes.Journal of neuroinflammation · 2024Article
- Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Article
- Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.Nature communications · 2023Article
- The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration.International journal of molecular sciences · 2023Article
- Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer's Disease Condition.Journal of Alzheimer's disease : JAD · 2023Review
- The Role of Cathepsin B in Pathophysiologies of Non-tumor and Tumor tissues: A Systematic Review.Journal of Cancer · 2023Review
- S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders.Cell death and differentiation · 2022Article
- Caspase-1 and Cathepsin B Inhibitors from Marine Invertebrates, Aiming at a Reduction in Neuroinflammation.Marine drugs · 2022Article
- Discovery of pH-Selective Marine and Plant Natural Product Inhibitors of Cathepsin B Revealed by Screening at Acidic and Neutral pH Conditions.ACS omega · 2022Article
- Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders.Pharmacological reviews · 2022Review
- Lysosomal peptidases-intriguing roles in cancer progression and neurodegeneration.FEBS open bio · 2022Review
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5 authors at 3 institutions in 1 country.
Funding
Abstract
Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer's disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.
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