Role of the APP Non-Amyloidogenic Signaling Pathway and Targeting α-Secretase as an Alternative Drug Target for Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent form of dementia, and its effective disease modifying therapies are desperately needed. Promotion of non-amyloidogenic alpha (α)-secretase cleavage of amyloid precursor protein (APP) to release soluble sAPPα, based on the most widely accepted “amyloid model” as a plausible mechanism for AD treatment, is the focus of this review. Modulation of α-secretase or “a disintegrin and metalloprotease (ADAM)”s activity via protein kinase C (PKC), calcium ion (Ca2+), tyrosine kinase (TK), MAP kinase (MAPK), and hormonal signaling, which regulate catabolic processing of APP, are discussed. The inhibition of amyloidogenic processing of APP by the beta (β)-and gamma (γ)-secretase has been considered till now a promising strategy to treat AD. But β- and γ-secretase inhibitors, along with the available therapeutic tools for AD, have side effects. These challenges can be circumvented to certain extent; but activation of sAPPα release appears to be a potential alternative strategy to reduce cerebral amyloidosis. Drug screens have been performed to identify therapeutics for AD, but an effective screening strategy to isolate activators of α-secretase has been rarely reported. Novel reporter-based screens targeted toward APP mRNA 5' untranslated region (UTR), followed by counterscreens to detect α-secretase stimulators, could be important in detecting compounds to promote sAPPα release and reduce amyloid beta (Aβ) buildup. The primary inflammatory cytokine interleukin-1, which stimulates APP 5'UTR-directed translation of cell-associated APP, enhances processing to sAPPα in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK signaling; thus illustrating a novel pathway that could serve as therapeutic model for AD.