Brain S‐Adenosylmethionine Levels Are Severely Decreased in Alzheimer's Disease

Abstract

S-Adenosylmethionine is an essential ubiquitous metabolite central to many biochemical pathways, including transmethylation and polyamine biosynthesis. Reduced CSF S-adenosylmethionine levels in Alzheimer'sdisease have been reported; however, no information is available regarding the status of Sadenosylmethionine or S-adenosylmethionine-dependent methylation in the brain of patients with this disorder. S-Adenosylmethionine concentrations were measured in postmortem brain of 11 patients with Alzheimer's disease. We found decreased levels of S-adenosylmethionine(-67to -85%) and its demethylated product S-adenosylhomocysteine (-56 to -79%) in all brain areas examined (cerebral cortical subdivisions, hippocampus, and putamen) as compared with matched controls (n = 14). S-Adenosylmethionine and S-adenosylhomocysteine levels were normal in occipital cortex of patients with idiopathic Parkinson's disease (n = 10), suggesting that the decreased Sadenosylmethionine levels in Alzheimer's disease are not simply a consequence of a chronic, neurodegenerative condition. Reduced S-adenosylmethionine levels could be due to excessive utilization in polyamine biosynthesis. The severe reduction in levels of this essential biochemical substrate would be expected to compromise seriously metabolism and brain function in pa-

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

“…Widely confirmed reports indicate that SAM dependent reactions are compromised in age related diseases due to impaired SAM metabolism [13,[26][27]. For these reasons, nutritional supplements restoring one-carbon metabolism alterations could restore physiological gene expression and oxidative buffering capacity, driving biochemical reactions to prevent or ameliorate degenerative processes.…”

“…Normal functioning of this metabolic cycle is essential for growth and development and impairment of this metabolism; transmethylation efficiency is associated with many diseases like cardiovascular diseases [4][5], liver diseases [6][7][8][9], neural tube defects [10] and brain diseases [11][12][13][14][15][16]. One-carbon metabolism alterations, low methylation and oxidative stress are all linked to Late Onset Alzheimer's Disease (LOAD) [17][18][19][20][21][22][23][24] Moreover, wide confirmed reports underline the role of SAM dependent reactions in age related neurodegeneration also showing the role of SAM supplementation in restoring one-carbon metabolism alterations, particularly in neurodegenerative diseases [25][26][27][28][29]. SAM is currently marketed as a nutritional supplement worldwide, whereas it is sold as a prescription drug in several countries of the European Union.…”

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

“…One important enzyme involved in FA generation by deamination is semicarbazide-sensitive amine oxidase (SSAO). SSAO, a copper-containing enzyme, is located primarily in cardiovascular smooth muscle, cartilage and other organs including the lung, liver, duodenum, kidney, and adrenal gland, and is circulated in the blood (Morrison et al, 1996;Yu et al, 1997;Mahy et al, 2001). The main substrates of SSAO are aromatic and aliphatic amines, which are deaminated into ammonia, hydrogen peroxide and FA as final products (Mahy et al, 2001;Conklin et al, 2004).…”

“…With aging, dysfunction of these enzymes may cause abnormalities in the formaldehyde cycle and aberrant enzymatic production of FA from endogenous and exogenous substrates results in the accumulation of FA, leading to stress and subsequent pathogenic neurodegeneration (Morrison et al, 1996;Tyihak et al, 1998;Kamino et al, 2000;Yu et al, 2003b;Unzeta et al, 2005;Unzeta et al, 2007). Other factors in aging can also produce excess endogenous FA.…”

Alzheimer’s Disease: Adult-Onset of Inborn Error of Methionine Metabolism

“…The source for such elevated homocysteine levels still remains obscure, but it could arise from the direct metabolism of methionine to homocysteine. It is also noteworthy that blood and brain concentrations of S-adenosylmethionine (SAM), an important biochemical for normal homeostasis, are severely depressed in AD patients [9]. The basis for this occurrence could be the unavailability of methionine to form SAM.…”