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Novel Cathepsin D Inhibitors Block the Formation of Hyperphosphorylated Tau Fragments in Hippocampus
Author(s) -
Bi Xiaoning,
Haque Tasir S.,
Zhou Jun,
Skillman A. Geoffrey,
Lin Bin,
Lee Christine E.,
Kuntz Irwin D.,
Ellman Jonathan A.,
Lynch Gary
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741469.x
Subject(s) - cathepsin d , cathepsin , cathepsin b , chemistry , hippocampal formation , alzheimer's disease , hippocampus , biochemistry , microbiology and biotechnology , neuroscience , biology , enzyme , disease , medicine
Lysosomal 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.