Table 3.

Association of SAM (metabolism) and transmethylation pathway with neurodegenerative disease in late stage

Disease	Condition	Target	Methylation effect	Read-out	Cell/tissue	Reference
	Folate and Vitamin B12 deficiency	PSEN1 BACE	↓	SAM/SAH↓; PSEN-1 and BACE↑; Aβ↑	SK-N-BE neuroblastoma cells	[6, 139]
	B vitamin deprivation	PSEN1 BACE	↓	SAM/SAH↓; PSEN-1 and BACE↑; Aβ↑	TgCRND8 mice	[141]
	B vitamin deficiency	GSK3β	↓	GSK3β↑;PP2A activity↓; phosphorylated tau↑	SK-N-BE cells	[142]
	SAH (SAM and PPMT)	PP2Ac PP2A	↓ ↓ (↑)	Tau phosphorylation↑; APP phosphorylation at Thr-668↑; β-Secretase-cleaved APP fragments↑ Aβ peptides↑ (tau dephosphorylation↑; α-secretase-cleaved APP fragment↑)	TgCRND8 mice Neuro-2a cells	[148]
	High-methionine, low-folate diet	PP2A	↓	PPMT↓;LCMT-1↓; demethylated PP2ABα↓	Cystathionine-β-synthase +/– mice	[173]
	Folate deficiency, folate-deficient diets	PP2A	↓	Phosphorylated tau↑	Neuro-2a cells C57BL/6J mice	[174]
	Methotrexate			Phosphorylated tau↑	Rat primary neuron cells	[175]

SAH = S-adenosylhomocysteine; PSEN-1 = presenilin 1; BACE = β-site amyloid precursor protein-cleaving enzyme; Aβ = amyloid β; SK-N-BE = ??; PP2A = protein phosphatase 2A; APP = amyloid precursor protein; PPMT = PP2A methyltransferases; LCMT-1 = leucine carboxyl methyltransferases 1