Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.

The pathophysiology of Alzheimer's disease (AD) is characterized by the formation of cerebral β-amyloid plaque from a small peptide amyloid-β (Aβ). Aβ is generated from the canonical amyloid-β precursor protein (APP) proteolysis pathway through β- and γ-secretases. Decreasing Aβ levels through targeting APP processing is a very promising direction in clinical trials for AD. A novel APP processing pathway was recently identified, in which η-secretase processing of APP occurs and results in the generation of the carboxy-terminal fragment-η (CTF-η or η-CTF) (Wang et al., 2015) and Aη-α peptide (Willem et al., 2015). η-Secretase processing of APP may be up-regulated by at least two mechanisms: either through inhibition of lysosomal-cathepsin degradation pathway (Wang et al., 2015) or through inhibition of BACE1 that competes with η-secretase cleavage of APP (Willem et al., 2015). A thorough characterization of η-processing of APP is critical for a better understanding of AD pathogenesis and insights into results of clinical trials of AD. Here we further investigated η-secretase processing of APP using well-characterized cell models of AD. We found that these two mechanisms act synergistically toward increasing η-secretase processing of APP and Aη-α levels. Furthermore, we evaluated the effects of several other known secretase modulators on η-processing of APP. The results of our study should advance the understanding of pathophysiology of AD, as well as enhance the knowledge in developing effective AD treatments or interventions related to η-secretase processing of APP.