Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment

Abstract

Introduction: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST).

Methods: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mutation in Aβ (APP_ArcSwe).

Results: Our findings demonstrate a significant increase in neprilysin levels, which correlates with a reduction in various forms of Aβ, including membrane-bound and intracellular Aβ aggregates, as well as Aβ42 in insoluble aggregates.

Discussion: These results suggest that neprilysin can effectively degrade Aβ with the Arctic mutation. Additionally, this treatment strategy successfully reduces both oligomeric and larger Aβ, aggregates, a challenge for other therapeutic approaches. This novel strategy holds promise as a potential therapeutic approach for AD.

Keywords: A11; Aggregation; Alzheimer’s disease; Amyloid beta; BBB; Biologicals; Blood brain barrier; Degradation; Hairpin; MME; Neprilysin; Oligomers; Protein pharmaceutics; SST; Somatostatin; TfR; Transferrin receptor; Transport.