Methotrexate decreases PP2A methylation and increases tau phosphorylation in neuron.
Folate deficiency is associated with Alzheimer's disease (AD) and has been suggested to contribute to the pathogenesis of AD. Hyperphosphorylation of tau and deposition of beta-amyloid derived from amyloid precursor protein (APP) are characteristic features of the neurodegenerative pathology of AD. To investigate the molecular mechanisms underlying the association between folate deficiency and AD pathogenesis, we treated rat primary neuron cultures with methotrexate (MTX), a folate antagonist. After MTX treatment, levels of phosphorylated tau, APP, and beta-secretase were increased, as shown by Western-blot and immunocytochemistry analyses, and the neuronal viability was reduced, as assessed by the MTS assay, indicating that folate deficiency increases characteristic AD pathologies. Interestingly, levels of methylated protein phosphatase-2A (PP2A), which is the active form of the putative tau phosphatase PP2A, were reduced. These novel findings indicate that folate deficiency increases the characteristic AD pathology including tau phosphorylation presumably by PP2A inactivation.
Yoon
Seung Yong
SY
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 PoongNap-Dong, SongPa-Gu, Seoul 138-736, Republic of Korea.
Choi
Hyo In
HI
Choi
Jung Eun
JE
Sul
Chang Ahn
CA
Choi
Jin Myoung
JM
Kim
Dong Hou
DH
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D007150:Immunohistochemistry; D008727:Methotrexate / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D054648:Protein Phosphatase 2; D053829:Amyloid Precursor Protein Secretases; D008727:Methotrexate