Mechanisms of Enzymatic Degradation of Amyloid β Microfibrils Generating Nanofilaments and Nanospheres Related to Cytotoxicity.

Amyloid β (Aβ) fibrils are found in the brain tissue of persons with Alzheimer's disease (AD), where they accumulate as plaques. One way to reduce the level of accumulation of Aβ in the brain and potentially treat AD is with Aβ-degrading enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, enzymatic responses and degradation mechanisms of Aβ fibrils (crystalline-state Aβ) have not been investigated, particularly with respect to how to avoid cytotoxicity of the degradation products to neuronal cells. Thus, insight into mechanisms of enzymatic degradation of Aβ fibrils would be instructive as a route to elucidating different structural features related to degradation and to cytotoxicity. We report mechanisms of enzymatic degradation of Aβ with cross-β structures and show the series of steps involved in the digestion of Aβ microfibrils to nanospheres or nanofilaments by protease XIV or α-chymotrypsin. respectively. These degradation products, which contained almost the same secondary structures, exhibited different cytotoxicities, indicating that relationships between nanoassembled structures and cytotoxicity of Aβ peptides are more significant than the β-sheet content. In addition, the enzymatic digestion at the Lys28 loop region linking the two β-sheets in Aβ fibrils is suggested as a key target related to cytotoxicity, a feature that can be selectively targeted on the basis of the choice of protease. [ABSTRACT FROM AUTHOR]