TY - JOUR
T1 - Reduced amyloid-β degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models
AU - Stargardt, Anita
AU - Gillis, Judith
AU - Kamphuis, Willem
AU - Wiemhoefer, Anne
AU - Kooijman, Lieneke
AU - Raspe, Marcel
AU - Benckhuijsen, Willemien
AU - Drijfhout, Jan W.
AU - Hol, Elly M.
AU - Reits, Eric
PY - 2013
Y1 - 2013
N2 - Alzheimer's disease (AD) is hallmarked by amyloid-β (Aβ) peptides accumulation and aggregation in extracellular plaques, preceded by intracellular accumulation. We examined whether intracellular Aβ 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 Aβ peptide that becomes fluorescent upon degradation was used to screen for Aβ-degrading cytoplasmic peptidases cleaving the aggregation-prone KLVFF region of the peptide. In addition, this quenched peptide was used to analyze Aβ-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 Aβ. Oligomerization of Aβ prevents its clearance by IDE. Intriguingly, the Aβ-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 Aβ degradation and IDE levels with AD progression, raising doubts whether mouse models that overproduce Aβ peptides are representative for human sAD
AB - Alzheimer's disease (AD) is hallmarked by amyloid-β (Aβ) peptides accumulation and aggregation in extracellular plaques, preceded by intracellular accumulation. We examined whether intracellular Aβ 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 Aβ peptide that becomes fluorescent upon degradation was used to screen for Aβ-degrading cytoplasmic peptidases cleaving the aggregation-prone KLVFF region of the peptide. In addition, this quenched peptide was used to analyze Aβ-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 Aβ. Oligomerization of Aβ prevents its clearance by IDE. Intriguingly, the Aβ-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 Aβ degradation and IDE levels with AD progression, raising doubts whether mouse models that overproduce Aβ peptides are representative for human sAD
U2 - https://doi.org/10.1111/acel.12074
DO - https://doi.org/10.1111/acel.12074
M3 - Article
C2 - 23534431
SN - 1474-9718
VL - 12
SP - 499
EP - 507
JO - Aging cell
JF - Aging cell
IS - 3
ER -