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A High Methionine, Low Folate and Low Vitamin B6/B12 Diet Causes Neurovascular Dysfunction and Subsequent Short‐Term Memory Loss

Methionine is an amino acid found in rich quantities in proteinaceous foods such as meats, fish and eggs. This essential amino acid is high in the average American diet due to protein consumption that far exceeds the daily requirement. Besides previous studies showing a correlation between high methionine and osteoporosis, heart attacks and pregnancy complications, more recent studies are showing links between high methionine and neurodegenerative disorders such as Alzheimer's and dementia. However, the mechanisms of methionine's effects are not clear. Therefore, this study is focused on the effects of a high methionine diet on neuronal and vascular function in the brain. 8–10 week old C57BL6/J male mice were fed with a methionine enriched (1.2%), low folate (0.08mg/Kg), and low vitamin B6 (0.01mg/Kg) and B12 (10.4 μg/Kg) diet for a 6 week period. Neuronal density and their degeneration were evaluated by assessing levels of Neuronal nuclear antigen and Neuron‐specific enolase (NSE), while vascular permeability was evaluated by assessing levels of endothelial junction proteins Vascular Endothelial‐Cadherin (VE‐Cadherin) and Claudin‐5 in harvested brain tissue. Cerebrovascular permeability was assessed by evaluating microvascular leakage of fluorescently‐labeled albumin in vivo. Cognitive function of mice was determined by measuring short‐term memory using a Novel Object Recognition test (NORT). Western blot and Immuno‐histochemical analyses of neuronal‐degeneration and vascular junction markers revealed a weekly increase in neuronal and vascular damage in mice on the diet. A significant increase in neuronal damage (Integrated optical density (IOD) of NSE/GAPDH: 1.39 +/− 0.01) was found in mice on the diet for 4 weeks compared to that (IOD of NSE/GAPDH: 0.99 +/−0.02) in control animals. Vascular albumin leakage was increased and VE‐cadherin levels (IOD of VE‐cadherin/GAPDH: 0.28 +/− 0.05) was decreased in mice on diet for 6 weeks compared to vascular leakage and VE‐cadherin levels (IOD of VE‐cadherin/GAPDH: 0.48 +/− 0.02) in control mice. NORT showed a decrease in short‐term memory (discrimination index (DI): 0.45 +/− 0.15) in mice on diet for 4 weeks compared to the wild‐type control group (DI: 0.89 +/−0.13). Collectively, our results suggest that a diet containing high methionine, low folate and low vitamin B6/B12 results in increased neuronal degeneration and vascular dysfunction, leading to short‐term memory loss. Interestingly, significant neuronal damage precedes vascular dysfunction.