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Article: Novel cathepsin D inhibitors block the formation of hyperphosphorylated tau fragments in hippocampus

TitleNovel cathepsin D inhibitors block the formation of hyperphosphorylated tau fragments in hippocampus
Authors
KeywordsSpecies Index: Animalia
Hippocampus Hippocampus
Issue Date2000
PublisherBlackwell Publishing Ltd
Citation
Journal of Neurochemistry, 2000, v. 74 n. 4, p. 1469-1477 How to Cite?
AbstractLysosomal disturbances may be a contributing factor to Alzheimer's disease. We used novel compounds to test if suppression of the lysosomal protease cathepsin D blocks production of known precursors to neurofibrillary tangles. Partial lysosomal dysfunction was induced in cultured hippocampal slices with a selective inhibitor of cathepsins B and L. This led within 48 h to hyperphosphorylated tau protein fragments recognized by antibodies against human tangles. Potent nonpeptidic cathepsin D inhibitors developed using combinatorial chemistry and structure-based design blocked production of the fragments in a dose-dependent fashion. Threshold was in the submicromolar range, with higher concentrations producing complete suppression. The effects were selective and not accompanied by pathophysiology. Comparable results were obtained with three structurally distinct inhibitors. These results support the hypothesis that cathepsin D links lysosomal dysfunction to the etiology of Alzheimer's disease and suggest a new approach to treating the disease.
Persistent Identifierhttp://hdl.handle.net/10722/91090
ISSN
2015 Impact Factor: 3.842
2015 SCImago Journal Rankings: 2.021
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorBi, Xen_HK
dc.contributor.authorHaque, TSen_HK
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorSkillman, AGen_HK
dc.contributor.authorLin, Ben_HK
dc.contributor.authorLee, CEen_HK
dc.contributor.authorKuntz, IDen_HK
dc.contributor.authorEllman, JAen_HK
dc.contributor.authorLynch, Gen_HK
dc.date.accessioned2010-09-17T10:12:53Z-
dc.date.available2010-09-17T10:12:53Z-
dc.date.issued2000en_HK
dc.identifier.citationJournal of Neurochemistry, 2000, v. 74 n. 4, p. 1469-1477en_HK
dc.identifier.issn0022-3042en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91090-
dc.description.abstractLysosomal disturbances may be a contributing factor to Alzheimer's disease. We used novel compounds to test if suppression of the lysosomal protease cathepsin D blocks production of known precursors to neurofibrillary tangles. Partial lysosomal dysfunction was induced in cultured hippocampal slices with a selective inhibitor of cathepsins B and L. This led within 48 h to hyperphosphorylated tau protein fragments recognized by antibodies against human tangles. Potent nonpeptidic cathepsin D inhibitors developed using combinatorial chemistry and structure-based design blocked production of the fragments in a dose-dependent fashion. Threshold was in the submicromolar range, with higher concentrations producing complete suppression. The effects were selective and not accompanied by pathophysiology. Comparable results were obtained with three structurally distinct inhibitors. These results support the hypothesis that cathepsin D links lysosomal dysfunction to the etiology of Alzheimer's disease and suggest a new approach to treating the disease.en_HK
dc.languageengen_HK
dc.publisherBlackwell Publishing Ltden_HK
dc.relation.ispartofJournal of Neurochemistryen_HK
dc.subjectSpecies Index: Animaliaen_HK
dc.subjectHippocampus Hippocampusen_HK
dc.titleNovel cathepsin D inhibitors block the formation of hyperphosphorylated tau fragments in hippocampusen_HK
dc.typeArticleen_HK
dc.identifier.emailLin, B:blin@hku.hken_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1046/j.1471-4159.2000.0741469.xen_HK
dc.identifier.pmid10737603-
dc.identifier.scopuseid_2-s2.0-0034030039en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034030039&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume74en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1469en_HK
dc.identifier.epage1477en_HK
dc.identifier.isiWOS:000085951400016-

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