Abstract
The relative increase in Aβ42 peptides from familial Alzheimer disease (FAD) linked APP and PSEN mutations can be related to changes in both ε-cleavage site utilization and subsequent step-wise cleavage. Cleavage at the ε-site releases the amyloid precursor protein (APP) intracellular domain (AICD), and perturbations in the position of ε-cleavage are closely associated with changes in the profile of amyloid β-protein (Aβ) species that are produced and secreted. The mechanisms by which γ-secretase modulators (GSMs) or FAD mutations affect the various γ-secretase cleavages to alter the generation of Aβ peptides have not been fully elucidated. Recent studies suggested that GSMs do not modulate ε-cleavage of APP, but the data were derived principally from recombinant truncated epitope tagged APP substrate. Here, using full length APP from transfected cells, we investigated whether GSMs modify the ε-cleavage of APP under more native conditions. Our results confirmed the previous findings that ε-cleavage is insensitive to GSMs. In addition, fenofibrate, an inverse GSM (iGSM), did not alter the position or kinetics of ε-cleavage position in vitro. APH1A and APH1B, a subunit of the γ-secretase complex, also modulated Aβ42/Aβ40 ratio without any alterations in ε-cleavage, a result in contrast to what has been observed with PS1 and APP FAD mutations. Consequently, GSMs and APH1 appear to modulate γ-secretase activity and Aβ42 generation by altering processivity but not ε-cleavage site utilization.
Highlights
Accumulation of β-amyloid peptide (Aβ) aggregates in senile plaque is one of the pathological hallmarks of Alzheimer disease (AD), understanding the factors that regulate amyloid β-protein (Aβ)PLOS ONE | DOI:10.1371/journal.pone.0144758 December 17, 2015 γ-Secretase Modulators Activity Is Independent of ε-Cleavage ionization time of flight; non-steroidal anti-inflammatory drugs (NSAIDs), non-steroidal antiinflammatory drugs; PS, Presenilin; TMD, transmembrane domain.production, clearance, and aggregation has been a major focus of research [1]
We asked whether GSMs and inverse GSM (iGSM) shift ε-cleavage as a potential mechanism through which the level of Aβ42 peptides are reduced
Our results showed that GSMs did not alter the position of ε-cleavage in cells expressing wild type amyloid precursor protein (APP) or PS1, nor in cells overexpressing familial AD (FAD) associated APP or PS1 mutations
Summary
Accumulation of β-amyloid peptide (Aβ) aggregates in senile plaque is one of the pathological hallmarks of Alzheimer disease (AD), understanding the factors that regulate AβPLOS ONE | DOI:10.1371/journal.pone.0144758 December 17, 2015 γ-Secretase Modulators Activity Is Independent of ε-Cleavage ionization time of flight; NSAIDs, non-steroidal antiinflammatory drugs; PS, Presenilin; TMD, transmembrane domain.production, clearance, and aggregation has been a major focus of research [1]. Aβ peptides are heterogeneous, varying from 34–43 amino acids in length Both heterogeneity at the N- and C-termini have been described with Aβ ending at different C-terminal residues having received most attention. Aβ1–40, or Aβ40 as commonly named, consists of 40 amino acids in length and is the most abundant species. Aβ42, though a minor species, is highly aggregation-prone, more neurotoxic in culture, and has been hypothesized to be the pathogenic trigger of AD [12]. In support of the latter concept, familial AD (FAD) mutations in PSEN1 and PSEN2, and most FAD-linked mutations in APP genes consistently alter either the levels or profile Aβ peptides that are produced [13]. The APH1B isoform favors the production of longer amyloid species and modifies the Aβ42/Aβ40 ratio
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