Alzheimer's disease (AD) neuropathology is characterized by the accumulation of phosphorylated tau and
amyloid-beta peptides derived from the
amyloid precursor
protein (APP). Elevated blood levels of
homocysteine are a significant risk factor for many age-related diseases, including AD. Impaired
homocysteine metabolism favors the formation of
S-adenosylhomocysteine, leading to inhibition of
methyltransferase-dependent reactions. Here, we show that incubation of
neuroblastoma cells with
S-adenosylhomocysteine results in reduced methylation of
protein phosphatase 2A (PP2A), a major brain Ser/Thr
phosphatase, most likely by inhibiting PP2A
methyltransferase (PPMT). PP2A methylation levels are also decreased after ectopic expression of
PP2A methylesterase in Neuro-2a (N2a) cells. Reduced PP2A methylation promotes the downregulation of B alpha-containing
holoenzymes, thereby affecting PP2A substrate specificity. It is associated with the accumulation of both phosphorylated tau and APP
isoforms and increased secretion of
beta-secretase-cleaved APP fragments and
amyloid-beta peptides. Conversely, incubation of N2a cells with
S-adenosylmethionine and expression of PPMT enhance PP2A methylation. This leads to the accumulation of dephosphorylated tau and APP species and increased secretion of neuroprotective
alpha-secretase-cleaved APP fragments. Remarkably,
hyperhomocysteinemia induced in wild-type and
cystathionine-beta-synthase +/- mice by feeding a high-
methionine, low-
folate diet is associated with increased brain
S-adenosylhomocysteine levels, PPMT downregulation, reduced PP2A methylation levels, and tau and APP phosphorylation. We reported previously that downregulation of neuronal PPMT and PP2A methylation occur in affected brain regions from AD patients. The link between
homocysteine, PPMT, PP2A methylation, and key CNS
proteins involved in AD pathogenesis provides new mechanistic insights into this disorder.