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Increased Levels of Circulating Methylglyoxal Have No Consequence for Cerebral Microvascular Integrity and Cognitive
Eline Berends1,2, Philippe Vangrieken1,2, Naima Amiri1,2
1Faculty of Health Medicine and Life Sciences, Department of Internal Medicine, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands.
Abstract:
Diabetes and other age-related diseases are associated with an increased risk of cognitive impairment, but the underlying mechanisms remain poorly understood. Methylglyoxal (MGO), a by-product of glycolysis and a major precursor in the formation of advanced glycation end-products (AGEs), is increased in individuals with diabetes and other age-related diseases and is associated with microvascular dysfunction. We now investigated whether increased levels of circulating MGO can lead to cerebral microvascular dysfunction, blood-brain barrier (BBB) dysfunction, and cognitive impairment. Mice were supplemented or not with 50 mM MGO in drinking water for 13 weeks. Plasma and cortical MGO and MGO-derived AGEs were measured with UPLC-MS/MS. Peripheral and cerebral microvascular integrity and inflammation were investigated. Cerebral blood flow and neurovascular coupling were investigated with laser speckle contrast imaging, and cognitive tests were performed. We found a 2-fold increase in plasma MGO and an increase in MGO-derived AGEs in plasma and cortex. Increased plasma MGO did not lead to cerebral microvascular dysfunction, inflammation, or cognitive decline. This study shows that increased concentrations of plasma MGO are not associated with cerebral microvascular dysfunction and cognitive impairment in healthy mice. Future research should focus on the role of endogenously formed MGO in cognitive impairment.
Insights
High levels of circulating methylglyoxal (MGO) did not impair cognitive function or cerebral microvasculature in mice. This suggests MGO alone may not cause cognitive decline in healthy individuals.
Area of Science:
- Neuroscience
- Metabolic Diseases
- Aging Research
Background:
- Cognitive impairment risk increases with diabetes and age-related diseases.
- Methylglyoxal (MGO), a glycolysis byproduct, rises in these conditions and links to microvascular issues.
- The role of MGO in brain health, particularly the blood-brain barrier (BBB) and cognitive function, is unclear.
Purpose of the Study:
- To investigate if elevated circulating methylglyoxal (MGO) causes cerebral microvascular dysfunction, BBB breakdown, and cognitive impairment.
- To assess the impact of MGO supplementation on brain microvasculature and cognitive performance in mice.
Main Methods:
- Mice received 50 mM MGO in drinking water for 13 weeks.
- Measured plasma and cortical MGO and MGO-derived advanced glycation end-products (AGEs) using UPLC-MS/MS.
- Assessed peripheral and cerebral microvascular integrity, inflammation, cerebral blood flow, neurovascular coupling, and cognitive function.
Main Results:
- Plasma MGO levels doubled, and MGO-derived AGEs increased in plasma and cortex.
- No significant cerebral microvascular dysfunction or inflammation was observed.
- Cognitive performance remained unaffected by MGO supplementation.
Conclusions:
- Elevated plasma methylglyoxal (MGO) concentrations are not associated with cerebral microvascular dysfunction or cognitive impairment in healthy mice.
- This study suggests exogenous MGO may not be the primary driver of cognitive decline in the absence of other disease factors.
- Further research is needed to explore the impact of endogenously formed MGO on cognitive impairment.
