Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function.
Hyperhomocysteinemia is common in Alzheimer's disease and is negatively correlated with cognitive function. Hyperhomocysteinemia can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor. This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer's disease. SAH was significantly (26%) higher in prefrontal cortex of Alzheimer patients than normals. Brain homogenates from Alzheimer patients inhibited an exogenous methyltransferase 15% more than normal homogenates (P <.001). Brain SAH levels correlated (r=.508) with methyltransferase inhibition by brain homogenates. Methyltransferase inhibition by Alzheimer brain homogenates correlated inversely with cognitive function as determined by MMSE (r=-0.36). Phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) activities were more than 30% lower (P<0.001) in Alzheimer than normal brains. Brain PNMT activity correlated significantly with cognitive function (r=0.243), age of Alzheimer's onset (r=0.272), and choline acetyltransferase activity (r=0.333), but negatively with neurofibrillary tangles (r=-0.332). COMT activity also correlated significantly with cognitive function (r=0.324), age of disease onset (r=0.209), choline acetyltransferase activity (r=0.326), levels of synaptophysin (r=0.506), and negatively with tangles (r=-0.216 P=0.039). Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment.
Kennedy
B P
BP
Department of Medicine, University of California, San Diego Medical Center, San Diego, CA 92103-8341, USA. bpkennedy@ucsd.edu
Bottiglieri
T
T
Arning
E
E
Ziegler
M G
MG
Hansen
L A
LA
Masliah
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D003071:Cognition; D005260:Female; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D013997:Time Factors
D012435:S-Adenosylhomocysteine; D008780:Methyltransferases