Methylglyoxal-induced neuronal dysfunction: Linking diabetes to Alzheimer's disease through cytoskeletal disruption

Abstract

This study investigates how methylglyoxal affects Alzheimer's disease, which is common in patients with diabetes mellitus. Using SH-SY5Y cells as a model of AD, we investigated the effects of MGO on cell viability, morphology, inflammation, and stress responses. Exposure to MGO induces cytotoxicity, inflammation and oxidative stress that contribute to AD in diabetic patients. We analyzed how MGO (150–900 μM) affects SH-SY5Y cells and its effects on cell survival, gene expression, cytoskeletal integrity, stress indicators, and Aβ42 accumulation (dose- and time-dependent). MGO dramatically affected cell viability depending on the dose and exposure time. Cell death occurred via intrinsic (BAX, CASP9) and extrinsic (FAS, FASLG) apoptotic pathways. Markers related to insulin signaling such as INSR, IRS1, IRS2, SLC2A4, etc. were downregulated, whereas markers of inflammation such as TNF-α, IL-6 and oxidative markers such as HMOX1, G6PD, etc. were upregulated with MGO (P < 0.001). Changes in MAP2 and TUBB3 expression were associated with cytoskeletal damage (P < 0.01). High levels of Aβ42 and low SOD activity confirmed that oxidative stress was induced. LPS treatment exacerbated these effects (P < 0.01).

The results highlight the possible role of MGO in cognitive decline associated with diabetes and suggest the need for novel treatment against MGO-related neurotoxicity.