Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function

Abstract

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.

Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation

“…In support of this hypothesis are findings that SAM levels are reduced in brain tissue (Morrison et al, 1996) and CSF (Bottiglieri et al, 1991) from AD patients. Increased SAH levels in brain tissue from AD patients correlate with the inhibition of two CNS methyltransferase reactions (catechol-O-methyltransferase and phenylethanolamine-N-methyltransferase) and various markers of disease progression and cognitive impairment (Kennedy et al, 2004). However, a recent study failed to show significant differences in SAM, SAH, or folate levels in CSF from control and AD subjects (Mulder et al, 2005).…”

COMT genotype and cognitive function

“…Furthermore, decreased COMT activity in the prefrontal cortex of patients with dementia was associated with increased severity of disease and poorer cognition. 30 Thus, lower enzyme activity, which is commonly found in the Met/Met genotype, seems to be associated with cognitive impairment in late life.…”

Implication of Epigenetic Modifications in Neurodegenerative Disorders: Traces and Imprints

“…Mice undergoing motor neuron degeneration bear increased amounts of DNMT3a in the synaptic junctions. In addition, accumulation of 5 mC along with DNMT1 and 3a is often seen in apoptotic motor neurons (Figure 2) [55,56]. Further, RG108 and Procainamide induced inhibition of DNMTs protect the motor neurons from excessive DNA methylation (Figure 2).…”