Hsu_2025_Int.J.Biol.Macromol_307_141932

Alzheimer's Disease (AD) constitutes approximately 70 % of dementia cases and is the most prevalent form of dementia. Current therapeutic options, including acetylcholinesterase inhibitors and N-methyl d-aspartate (NMDA) receptor antagonists, provide symptomatic relief but do not cure the disease and often come with side effects. The primary pathological features of AD are amyloid plaques and neurofibrillary tangles, with amyloid plaques formed by the abnormal accumulation of Amyloid-beta (Abeta). BACE1 (beta-site APP-cleaving enzyme 1), a beta-secretase, is a key initiator in amyloidosis. Previous research has shown that G-Bro hydrolysate, produced from the bromelain hydrolysis of gliadin, has optimal BACE1 inhibitory efficiency. This study employs G-Bro hydrolysate for nano UHPLC-ESI Q-TOF mass spectrometry to identify peptide fragment sequences and conducts BACE1 inhibition assays to isolate the most effective peptide, VR-peptide. Using the N2a/PS/APP cell model, we explored the impact of chemically synthesized VR-peptide on BACE1 protein expression, the secretion of soluble APP (sAPP), and levels of Abeta and intracellular Abeta1-42. Results demonstrate that VR-peptide achieves a BACE1 inhibitory rate of 63.8 % and reduces BACE1 expression by over 90 % in comparison with untreated N2a/PS/APP cells. It shifts the balance between extracellular Abeta monomers and aggregates, favoring monomer formation and decreasing intracellular Abeta1-42 levels by over 56 %, underscoring its neuroprotective potential. In conclusion, VR-peptide exhibits promise as a BACE1 inhibitor and a preventive agent against Alzheimer's disease. Derived from hydrolyzed cereal foods, it could be effectively paired with a suitable drug delivery system for enhanced neuronal penetration, paving the way for neuroprotective peptide products targeting Alzheimer's disease.