Neprilysin-Mediated Amyloid Beta Clearance and Its Therapeutic Implications in Neurodegenerative Disorders

Neprilysin (NEP) is a neutral endopeptidase, important for the degradation of amyloid beta (Aβ) peptides and other neuropeptides, including enkephalins, substance P, and bradykinin, in the brain, that influences various physiological processes such as blood pressure homeostasis, pain perception, and neuroinflammation. NEP breaks down Aβ peptides into smaller fragments, preventing the development of detrimental aggregates such as Aβ plaques. NEP clears Aβ plaques predominantly by enzymatic breakdown in the extracellular space. However, NEP activity may be regulated by a variety of factors, including its expression and activity levels as well as interactions with other proteins or substances present in the brain. The Aβ de novo synthesis results from the amyloidogenic and nonamyloidogenic processing of the amyloid precursor protein (APP). In addition to Aβ synthesis, enzymatic degradation and various clearance pathways also contribute to the degradation of the monomeric form of Aβ peptides in the brain. Higher production, dysfunction of degradation enzymes, defective clearance mechanisms, intracellular accumulation of phosphorylated tau proteins, and extracellular deposition of Aβ are hallmarks of neurodegenerative diseases. Strategies for promoting NEP levels or activity, such as pharmaceutical interventions or gene therapy procedures, are being studied as possible therapies for neurodegenerative diseases including Alzheimer's disease. Therefore, in this perspective, we discuss the recent developments in NEP-mediated amyloidogenic and plausible mechanisms of nonamyloidogenic clearance of Aβ. We further highlight the current therapeutic interventions such as pharmaceutical agents, gene therapy, monoclonal antibodies, and stem-cell-based therapies targeting NEP for the management of neurodegenerative disorders.