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bioRxiv · 10.1101/2025.11.21.689865

Vascular dementia increases levels of methylenetetrahydro-folate reductase and cystathionine β-synthase in female patients and changes gene expression of acetylcholine and glutamate clathrin-sculpted transport vesicles

Joshi, S.·McKee, A.·Ille, S.·Buss, K.·Beach, T.·Serrano, G. E.·Jadavji, N. M.
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Abstract

Vascular dementia (VaD) is a complex clinical syndrome arising from cerebrovascular disease, characterized by cognitive decline and functional impairment, and is projected to double in prevalence over the next three decades. Deficiencies in one-carbon (1C) metabolism are linked to the onset of VaD. Our previous work using mouse models has demonstrated that reduced dietary folic acid intake or genetic disruptions in 1C metabolism exacerbate outcomes in a model of VaD. However, the impact of VaD on one-carbon metabolism remains poorly understood. This study aims to provide a detailed molecular portrait of 1C metabolism within the context of VaD, shedding light on potential molecular mechanisms. In post-mortem medial prefrontal cortex tissue from VaD female and male patients and controls we measured protein expression of the folate receptor (FR) and 1C enzymes including methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), cystathionine {beta}-synthase (CBS) co-localized with NeuN. There was an interaction between VaD and gender for levels of FR. Both male and female VaD had increased levels of ChAT. Female VaD patients had higher levels of MTHFR and CBS when compared to males. VaD is a complex disease; the results of this study demonstrate that VaD impacts neuronal levels of 1C enzymes. Future studies should assess 1C in other cell types of the brain, as well as measure enzyme activity levels.

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Joshi, S., McKee, A., Ille, S., Buss, K., Beach, T., Serrano, G. E., Jadavji, N. M.. 2025-11-25. Vascular dementia increases levels of methylenetetrahydro-folate reductase and cystathionine β-synthase in female patients and changes gene expression of acetylcholine and glutamate clathrin-sculpted transport vesicles. https://doi.org/10.1101/2025.11.21.689865

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