Selective suppression of cathepsin L results from elevations in lysosomal pH and is followed by proteolysis of tau protein.
Incubation of cultured hippocampal slices with chloroquine, a compound that increases the pH of acidic subcellular organelles, for 10 h reduced the activity of cathepsin L by 83 +/- 0.87% (mean +/- s.e.m.) while only marginally suppressing cathepsin B. This effect was followed within 3 h by an increase in the concentration of mature, single-chain cathepsin D (up 61 +/- 28%). Selective depression of cathepsin L with N-CBZ-L-phenylalanyl-L-phenylalanine-diazomethylketone also resulted in increases in enzymatically active cathepsin D and the delayed appearance of a 29 kDa fragment of the tau protein. These findings demonstrate that the pattern of cathepsin L, B, and D changes found in the aged brain can be reproduced by reducing the acidity of the lysosomal milieu. They also indicate that such pH shifts initiate a sequence of linked disturbances (inactivation of cathepsin L > induction of cathepsin D > aberrant tau proteolysis) likely to play an important role in brain ageing.
Bednarski
E
E
Center for the Neurobiology of Learning and Memory, University of California, Irvine 92697-3800, USA.
Lynch
G
G
D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases; D006624:Hippocampus / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D008247:Lysosomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D016875:tau Proteins; D002738:Chloroquine; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534280:Ctsl protein, rat; D002402:Cathepsin D