| First Author | Stargardt A | Year | 2013 |
| Journal | Aging Cell | Volume | 12 |
| Issue | 3 | Pages | 499-507 |
| PubMed ID | 23534431 | Mgi Jnum | J:352629 |
| Mgi Id | MGI:7663085 | Doi | 10.1111/acel.12074 |
| Citation | Stargardt A, et al. (2013) Reduced amyloid-beta degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models. Aging Cell 12(3):499-507 |
| abstractText | Alzheimer's disease (AD) is hallmarked by amyloid-beta (Abeta) peptides accumulation and aggregation in extracellular plaques, preceded by intracellular accumulation. We examined whether intracellular Abeta 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 Abeta peptide that becomes fluorescent upon degradation was used to screen for Abeta-degrading cytoplasmic peptidases cleaving the aggregation-prone KLVFF region of the peptide. In addition, this quenched peptide was used to analyze Abeta-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 Abeta. Oligomerization of Abeta prevents its clearance by IDE. Intriguingly, the Abeta-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 Abeta degradation and IDE levels with AD progression, raising doubts whether mouse models that overproduce Abeta peptides are representative for human sAD. |
