Cerebral Folate Metabolism in Post-Mortem Alzheimer's Disease Tissues: A Small Cohort Study

We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (n = 21) and neuropathologically normal brains (n = 21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FR alpha) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FR alpha switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FR alpha-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment.

Automated summary

We examined the cerebral folate system in AD and normal brains. Our findings demonstrate a significant reduction in FDH, FR alpha, and folate in the CSF of AD patients. Additionally, we observed a switch in the folate supply pathway in AD cortex, correlating with a metabolic direction towards neuronal hypermethylation. These findings provide insights into the cognitive decline in AD and suggest a potential treatment target.