Calpain inhibitor MDL28170 modulates Aβ formation by inhibiting the formation of intermediate Aβ46 and protecting Aβ from degradation

Y Dong, J Tan, MZ Cui, G Zhao, G Mao… - The FASEB …, 2006 - Wiley Online Library
Y Dong, J Tan, MZ Cui, G Zhao, G Mao, N Singh, X Xu
The FASEB journal, 2006Wiley Online Library
The observations that three major cleavages within the transmembrane domain of APP,
namely, the γ‐cleavage, ε‐cleavage, and the newly identified ζ‐cleavage, are involved in the
generation of secreted Aβ40 and Aβ42 prompted us to determine how the calpain inhibitor III
MDL 28170 influences these three cleavages and Aβ formation. With the use of a cell culture
system, our data demonstrate that 1) at either high concentrations, or at a low range of
concentrations, at early time points, MDL 28170 inhibits the formation of secreted Aβ40 and …
Abstract
The observations that three major cleavages within the transmembrane domain of APP, namely, the γ‐cleavage, ε‐cleavage, and the newly identified ζ‐cleavage, are involved in the generation of secreted Aβ40 and Aβ42 prompted us to determine how the calpain inhibitor III MDL 28170 influences these three cleavages and Aβ formation. With the use of a cell culture system, our data demonstrate that 1) at either high concentrations, or at a low range of concentrations, at early time points, MDL 28170 inhibits the formation of secreted Aβ40 and Aβ42. However, this effect is due to inhibition of the intermediate Aβ46 generation by ζ‐cleavage and not due to direct inhibition of the γ‐cleavage that produces Aβ40/42 from Aβ46; 2) at low range of concentrations and at late time points, MDL 28170 causes an increase in secreted Aβ40/42 that likely results from inhibition of degradation of both the initial substrate, CTFβ, and the final product, Aβ40/42, of γsecretase. These data strongly suggest that formation of Aβ46 is a key step in the γ‐secretase mediated generation of Aβ40/42 and provide a new target for the development of Aβ inhibitors. These data also suggest that calpain and related proteases, which are sensitive to MDL 28170, play an important role in the accumulation of secreted Aβ.
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