Fig. 4
From: Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease
Metabolic implications of methylation in neurons. The state of methylation potential in cells depends on the levels of methionine derived global methylation donor S-adenosyl methionine (SAM) or AdoMet and S-adenosyl homocysteine (SAH). SAM donates methyl group in various cellular processes such as myelination, neurotransmitter metabolism, phospholipid synthesis and protein/DNA methylation. SAH is formed upon methyl donation which gets hydrolyzed to homocysteine in a reversible reaction. Homocysteine can be remethylated in order to replenish the methionine pool or undergoes trans-sulfuration to produce cysteine or gets reconverted into SAH. Thus, the ratio of SAM: SAH determines the overall methylation potential with higher SAM levels favoring methylation. Increased levels of SAH tip the balance towards Homocysteine accumulation in CSF, which can serve as a marker for neurodegenerative conditions. Metabolic conditions which leads to lower SAM:SAH ratio decrease methylation potential in neurons and results in promoter hypomethylation of genes involved in AD viz. amyloid precursor protein (APP) and Presenilin 1 (PS1). Higher APP and PS1 levels gradually lead to protein aggregation and neurodegeneration