BETA-AMYLOID INCREASES CATHEPSIN-D LEVELS IN HIPPOCAMPUS

A previous study established that beta-amyloid(1-42), is sequestered a nd retained intact for extended periods by select populations of neuro ns in cultured hippocampal slices. The present experiment tested if th is effect is accompanied by increases in cathepsin D, a characteristic feature of lysosomal dysfunction and one that has been implicated in key aspects of brain aging in humans. Slices incubated with beta-amylo id(1-42), (15-30 mu M) for 6 days had 56% greater concentrations of ca thepsin D than controls. Scrambled peptides had no effect. The amyloid -induced increase was additive with that produced by submaximal concen trations of an inhibitor of cathepsins B and L but occluded that cause d by chloroquine. This pattern of results (1) indicates that the uptak e of amyloid results in lysosomal dysfunction and (2) suggests that pe rturbations of intralysosomal pH may contribute to this effect. (C) 19 98 Elsevier Science Ireland Ltd. All rights reserved.