review · Journal of Cellular and Molecular Medicine
Neprilysin is an essential enzyme involved in the degradation and clearance of amyloid beta, a protein that accumulates in the brains of individuals with Alzheimer's disease. Inhibiting neprilysin, such as through the combined drug sacubitril and valsartan, presents both harmful and beneficial possibilities for disease progression. In animal models, neprilysin inhibition reduces amyloid clearance and elevates brain bradykinin and natriuretic peptides, which may heighten the risk of Alzheimer's disease. In contrast, clinical studies demonstrate promising safety outcomes for these combined therapies. Additionally, neprilysin inhibitors can reduce dipeptidyl peptidase 4 expression and raise neuroprotective peptides such as glucagon-like peptide 1, substance P, and neuropeptide Y, which support glucose homeostasis, inflammation control, and nerve conduction. Overall, neprilysin inhibitors display a complex mix of neuroprotective and potentially damaging effects, necessitating further preclinical and clinical investigation.
Neprilysin inhibitors are already used in medicine, notably in cardiovascular therapies. Clarifying whether these drugs increase the risk of Alzheimer's disease or offer neuroprotective benefits is critical for patient safety and clinical decision-making. These insights help medical researchers understand how altering peptide degradation impacts neurodegeneration, metabolic regulation, and nerve function.
The abstract examines existing pharmacological agents, specifically the combination of sacubitril and valsartan, rather than introducing a new product. Pharmaceutical companies and clinical researchers could use these insights to assess the neurological safety of neprilysin inhibitors or evaluate their repurposing potential. Because evidence is currently limited to animal models and early clinical safety observations, any therapeutic application for Alzheimer's disease remains at an early exploratory stage.
AI-generated from the published abstract. Always read the original work before citing.
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.1111/jcmm.17993
Is something wrong with this record? Report it or request removal.
Discussion
Have you built on this work, tried to replicate it, or seen it applied in practice? Share what you know. Verified researchers and MARATTO™ domain experts can open a discussion, and any member can reply. Contributions are reviewed before they appear.
No discussion yet. Open the first thread.
New to MARATTO™? Create a free account.
