Fig. 1

Schematic presentation of proteolytic processing of the amyloid precursor protein (APP), the Aβ clearance mechanism, and the Aβ aggregation process which occurs via HNE modification. The proteolytic processing of the APP could be divided into two pathways: non-amyloidogenic and amyloidogenic. In the non-amyloidogenic pathway, APP is cleaved by α-secretase which results in the production of C83 and sAPPα. Ultimately, γ-secretase cleaves C83 and p3 is produced, which precludes Aβ aggregation. For the amyloidogenic pathway, APP is cleaved by β-secretase which results in the production of C99 and sAPPβ. Subsequently, the γ secretase cleaves C99 and produces AICD and Aβ peptides. Initial Aβ aggregation is considered as a hallmark pathology for diagnosing AD in the early stage (lag phase). In Aβ clearance, Aβ peptides are degraded via IDE and NEP proteases through microglial phagocytosis and peripheral Aβ clearance. However, oxidative stress can impair Aβ clearance through 4-hydroxynonenal (HNE) modification; HNE modification is the product of oxidative stress due to the presence of lipid peroxidation in the lag phase of AD. Oxidative stress reflects a redox imbalance, resulting from a combination of reactive oxygen species (ROS) and reactive nitrogen species (RNS) overweighing the antioxidants