Abstract
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 (FRα) 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. FRα 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 FRα-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.
Funder
Charles Wolfson Charitable Trust
The African Healthcare Development Trust
Commonwealth Scholarship Commission
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference94 articles.
1. Global prevalence of dementia: A Delphi consensus study;Ferri;Lancet,2005
2. History and progress of hypotheses and clinical trials for Alzheimer’s disease;Liu;Signal Transduct. Target. Ther.,2019
3. Vaccination Prevented Short-Term Memory Loss, but Deteriorated Long-Term Spatial Memory in Alzheimer’s Disease Mice, Independent of Amyloid-beta Pathology;Oberman;J. Alzheimer’s Dis. Rep.,2020
4. Mantile, F., and Prisco, A. (2020). Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer’s Disease. Biology, 9.
5. Therapy for Alzheimer’s disease: Missing targets and functional markers?;Stoiljkovic;Ageing Res. Rev.,2021
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献