Dietary Methylglyoxal Exposure Induces Alzheimer’s Disease by Promoting Amyloid β Accumulation and Disrupting Autophagy in Caenorhabditis elegans

Abstract

Methylglyoxal (MG) is a precursor of advanced glycation end products usually generated during cooking. The high level of MG in the brain is correlated to the pathogenesis of Alzheimer’s disease (AD). However, it is not clear if MG consumed through the diet can cause AD-related toxicity. Herein, the Caenorhabditis elegans (C. elegans) AD model was used to investigate the neurotoxicity after long-term MG exposure at dietary levels. The results showed that C. elegans locomotive behaviors were significantly decreased after 0.1, 0.5, and 1 mM MG exposure (p < 0.001). In amyloid β (Aβ)-expressing transgenic C. elegans strains, 0.5 mM MG significantly promoted Aβ accumulation by around 50% in day-8 CL2006 (p < 0.001), enhanced paralysis in CL4176 (p < 0.001) and CL2006 (p < 0.01), and made CL2355 around 17% more vulnerable to 5-HT, indicating impaired serotonin reuptake (p < 0.05). Additionally, 0.5 mM MG significantly increased the reactive oxygen species level (p < 0.001) by inhibiting the expression of stress-response genes including sod-3, gst-4, and hsp-16.2 in day-8 aged worms. Moreover, the autophagic pathway was disrupted through lgg-1, vps-34, and bec-1 expression after MG exposure and Aβ accumulation. Treatment with the citrus flavonoid nobiletin reduced the MG-induced toxicity (p < 0.001). Overall, these findings imply that it is possible to exacerbate AD pathogenesis by MG exposure through the diet.

RAGE Inhibitors in Neurodegenerative Diseases

“…These experiments suggested that the methylglyoxal, a precursor compound of AGEs, activates the membrane-bound NADPH oxidase (NOX), thereby leading to the expression of inflammatory markers, and the accompanying astroglial and microglial activation and synaptic dysfunction in animal models as well as in AD patients. Dietary methylglyoxal was also shown to induce AD through the increased expression of amyloid-β (Aβ) in AD models of Caenorhabiditis elegans ( C. elegans ) [ 87 ]. It was demonstrated that the use of a citrus flavonoid, nobiletin, attenuated the methylglyoxal-induced toxicity [ 87 ].…”

“…Dietary methylglyoxal was also shown to induce AD through the increased expression of amyloid-β (Aβ) in AD models of Caenorhabiditis elegans ( C. elegans ) [ 87 ]. It was demonstrated that the use of a citrus flavonoid, nobiletin, attenuated the methylglyoxal-induced toxicity [ 87 ]. Other polyphenolic compounds, including ss-caryophyllene and carnosic acid, and camellia oil were also demonstrated to show anti-inflammatory activity and thus act as potential neuroprotective compounds [ 85 , 88 , 89 ].…”

Glycation reactions of methylglyoxal during digestion in a dynamic, in vitro model of the upper gastrointestinal tract (TIM‐1)

“…The same cohort had less low‐grade inflammation in participants with a higher habitual intake of MGO (Maasen, Eussen, Dagnelie, et al., 2022 ). Prolonged exposure to high levels of MGO in animals induced various negative effects like decreased locomotive behavior and promoted amyloid β accumulation in Caenorhabditis elegans (Wei et al., 2022 ) and oxidative stress and endothelial dysfunction in rats (Sena et al., 2012 ). On the other hand, long‐term oral application of MGO had no adverse effects on physical performance and organs in rabbits, rats, mice, and dogs (Ghosh et al., 2006 ).…”