β-Amyloid (Aβ, a peptide generated by proteolytic cleavage of the amyloid precursor protein (APP), is a major constituent of the neuritic plaques associated with Alzheimer's disease (AD). Up-regulation of α-secretase, which can hydrolyze Aβ between Lys16 and Leu17, has been proposed as a potential therapeutic strategy in the treatment of AD. Previously, we identified two light-chain antibody fragments that had proteolytic activity against Aβ, one with α-secretase-like activity and one with carboxypeptidase-like activity. Here we show that cleavage of Aβ40 by hk14, the light-chain antibody having carboxypeptidase-like activity, alters aggregation of Aβ and neutralizes any cytotoxic effects of the peptide. Cleavage of Aβ40 with c23.5, the light chain having α-secretase-like cleavage, substantially increases the aggregation rate of Aβ however, it does not show any corresponding increase in cytotoxicity. The increase in aggregation resulting from hydrolysis by c23.5 can be attributed to the decreased solubility of the hydrolyzed products relative to the parent Aβ40, primarily the Aβ-40 fragment. These results demonstrate that antibody fragment mediated proteolytic degradation of Aβ peptide can be a potential therapeutic route to control Aβ aggregation and toxicity in vivo. Our results also suggest that increasing α-secretase activity as a therapeutic route must be approached with some caution because this can lead to a substantial increase in aggregation.
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