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

Abstract

SummaryAlzheimer's disease (AD) is hallmarked by amyloid-b (Ab) peptides accumulation and aggregation in extracellular plaques, preceded by intracellular accumulation. We examined whether intracellular Ab 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 Ab peptide that becomes fluorescent upon degradation was used to screen for Ab-degrading cytoplasmic peptidases cleaving the aggregation-prone KLVFF region of the peptide. In addition, this quenched peptide was used to analyze Ab-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 Ab. Oligomerization of Ab prevents its clearance by IDE. Intriguingly, the Ab-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 Ab degradation and IDE levels with AD progression, raising doubts whether mouse models that overproduce Ab peptides are representative for human sAD.

Improving the predictive value of interventional animal models data

“…These included descriptions of strain variation in processing of amyloid-beta [34], altered phenotype expression by strain [35–37], variations in behavioral testing by strain [38,39], species similarities [40] or differences in molecular signatures of the aging synapse [41], or aging brain [42,43], gender differences in amyloid plaque development within model [43,44] and differences in amyloid-beta degradation and toxicity between mice, humans and large animal models [45,46]. This type of normative data profoundly impacts study design and interpretation, and contributes to the species barrier [18].…”

The pattern of amyloid accumulation in the brains of adults with Down syndrome

“…Immunohistochemistry studies have shown that striatal plaques are predominantly, or entirely, composed of Aβ1–42 and Aβ1–43 [31] , [34] . Familial forms of AD and DS share overproduction of amyloid as the proposed mechanism of amyloid deposition [37] , whereas decreased clearance might be more significant in sporadic AD [38] . Therefore, it might be that the cellular milieu of the striatum is particularly vulnerable to early amyloid accumulation under the conditions of overproduction.…”

Metformin Ameliorates Aβ Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer’s Disease

“…The activity of IDE in the brain decreases with age and during early stages of AD. Overexpression of IDE in transgenic mice can prevent amyloid plaque formation [40]. Inhibition of IDE is identified as one of the crosstalk between T2D and AD [21].…”