Hyperglycemia-Driven Alterations in Amyloid β Metabolism and Neprilysin Expression: A Biochemical Link to Neurocomplexity of Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with neurological abnormalities, particularly in patients with prolonged disease duration. Given the similarities between diabetes and Alzheimer’s disease, amyloidogenic mechanisms may contribute to the pathogenesis of hyperglycemia; however, the precise roles of amyloid-related proteins and amyloid-β (Aβ) metabolism in diabetes-induced neural injury remain unclear. This study aimed to evaluate the involvement of Aβ-42, soluble amyloid precursor protein-α (sAPPα), β-secretase (BACE1), and neprilysin (NEP) in the pathogenesis of diabetes. For this purpose, the fasting blood samples from were prepared from patients with T2DM and age- and sex-matched healthy controls were analyzed for the levels of Aβ-42, sAPPα, BACE1, and NEP using enzyme-linked immunosorbent assay. Patients with T2DM showed remarkably higher FBS, HbA1c, insulin, and HOMA-IR values compared with controls. Serum level of Aβ-42 and BACE1 were significantly raised in T2DM group, whereas sAPPα levels were markedly downregulated. Blood concentration of NEP was increased in the T2DM and exhibited a positive correlation with HOMA-IR. According to the results, hyperglycemia promotes amyloidogenic APP processing and Aβ-42 accumulation, whereas the elevated NEP level may represent a compensatory response to increased Aβ production. These findings highlight a potential molecular link between T2DM and amyloid-associated neurodegeneration.