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Methylglyoxal-induced neuronal dysfunction: Linking diabetes to Alzheimer's disease through cytoskeletal disruption
Majid Tozihi1, Alireza Nourazarian2, Hadi Yousefi2
1Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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.
Insights
Methylglyoxal (MGO) exposure causes cell death and inflammation, contributing to Alzheimer's disease (AD) in diabetic patients. This study reveals MGO's neurotoxic effects, suggesting new therapeutic targets for diabetes-related cognitive decline.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Alzheimer's disease (AD) is prevalent in diabetic patients.
- Methylglyoxal (MGO) is a reactive dicarbonyl compound implicated in diabetic complications.
Purpose of the Study:
- To investigate the neurotoxic effects of MGO on SH-SY5Y cells, a model for AD.
- To elucidate the mechanisms underlying MGO-induced cytotoxicity, inflammation, and oxidative stress.
Main Methods:
- SH-SY5Y cells were exposed to varying concentrations of MGO (150-900 μM).
- Assessed cell viability, morphology, apoptosis (intrinsic and extrinsic pathways), gene expression (insulin signaling, inflammation, oxidative stress markers), cytoskeletal integrity, Aβ42 accumulation, and SOD activity.
- Lipopolysaccharide (LPS) treatment was used to exacerbate MGO effects.
Main Results:
- MGO exposure significantly reduced cell viability in a dose- and time-dependent manner.
- MGO induced apoptosis via intrinsic (BAX, CASP9) and extrinsic (FAS, FASLG) pathways.
- Downregulation of insulin signaling markers (INSR, IRS1, IRS2, SLC2A4) and upregulation of inflammation (TNF-α, IL-6) and oxidative stress markers (HMOX1, G6PD) were observed.
- Cytoskeletal damage (MAP2, TUBB3), increased Aβ42 levels, and decreased SOD activity confirmed MGO-induced neurotoxicity and oxidative stress.
- LPS treatment worsened MGO-induced effects.
Conclusions:
- MGO plays a significant role in the neurotoxicity observed in diabetes-associated AD.
- MGO induces cytotoxicity, inflammation, and oxidative stress, contributing to cognitive decline.
- Targeting MGO-related neurotoxicity presents a potential therapeutic strategy for managing cognitive impairment in diabetic patients.
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