The transmethylation cycle in the brain of Alzheimer patients.
Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.
Mulder
Cees
C
Department of Clinical Chemistry, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. c.mulder@vumc.nl
Schoonenboom
Niki S M
NS
Jansen
Erwin E W
EE
Verhoeven
Nanda M
NM
van Kamp
Gerard J
GJ
Jakobs
Cornelis
C
Scheltens
Philip
P
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D008745:Methylation; D008875:Middle Aged; D053764:Presenilin-1; D011401:Promoter Regions, Genetic; D012435:S-Adenosylhomocysteine / Q000134:cerebrospinal fluid* / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000134:cerebrospinal fluid* / Q000378:metabolism; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid* / Q000378:metabolism
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D013763:Tetrahydrofolates; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; C005984:5-methyltetrahydrofolate