Reduced amyloid- degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models

Alzheimer's disease (AD) is hallmarked by amyloid- (A) peptides accumulation and aggregation in extracellular plaques, preceded by intracellular accumulation. We examined whether intracellular A can be cleared by cytosolic peptidases and whether this capacity is affected during progression of sporadic AD (sAD) in humans and in the commonly used APPswePS1dE9 and 3xTg-AD mouse models. A quenched A peptide that becomes fluorescent upon degradation was used to screen for A-degrading cytoplasmic peptidases cleaving the aggregation-prone KLVFF region of the peptide. In addition, this quenched peptide was used to analyze A-degrading capacity in the hippocampus of sAD patients with different Braak stages as well as APPswePS1dE9 and 3xTg-AD mice. Insulin-degrading enzyme (IDE) was found to be the main peptidase that degrades cytoplasmic, monomeric A. Oligomerization of A prevents its clearance by IDE. Intriguingly, the A-degrading capacity decreases already during the earliest Braak stages of sAD, and this decline correlates with IDE protein levels, but not with mRNA levels. This suggests that decreased IDE levels could contribute to early sAD. In contrast to the human data, the commonly used APPswePS1dE9 and 3xTg-AD mouse models do not show altered A degradation and IDE levels with AD progression, raising doubts whether mouse models that overproduce A peptides are representative for human sAD.