S-Adenosylmethionine and Superoxide Dismutase 1 Synergistically Counteract Alzheimer’s Disease Features Progression in TgCRND8 Mice

Abstract

Recent evidence emphasizes the role of dysregulated one-carbon metabolism in Alzheimer’s Disease (AD). Exploiting a nutritional B-vitamin deficiency paradigm, we have previously shown that PSEN1 and BACE1 activity is modulated by one-carbon metabolism, leading to increased amyloid production. We have also demonstrated that S-adenosylmethionine (SAM) supplementation contrasted the AD-like features, induced by B-vitamin deficiency. In the present study, we expanded these observations by investigating the effects of SAM and SOD (Superoxide dismutase) association. TgCRND8 AD mice were fed either with a control or B-vitamin deficient diet, with or without oral supplementation of SAM + SOD. We measured oxidative stress by lipid peroxidation assay, PSEN1 and BACE1 expression by Real-Time Polymerase Chain Reaction (PCR), amyloid deposition by ELISA assays and immunohistochemistry. We found that SAM + SOD supplementation prevents the exacerbation of AD-like features induced by B vitamin deficiency, showing synergistic effects compared to either SAM or SOD alone. SAM + SOD supplementation also contrasts the amyloid deposition typically observed in TgCRND8 mice. Although the mechanisms underlying the beneficial effect of exogenous SOD remain to be elucidated, our findings identify that the combination of SAM + SOD could be carefully considered as co-adjuvant of current AD therapies.

Vitamin B6 and Its Role in Cell Metabolism and Physiology

“…The biosynthesis of epinephrine, serotonin, and dopamine is independently influenced by a universal methyl donor, S-adenosylmethionine (SAM), a critical intermediate in the methionine-cycle [ 140 , 155 , 156 , 157 , 158 , 159 , 160 ] ( Figure 5 ). Consequently, several studies have shown that a deficiency in vitB 6 correlates with a deficiency in folate and cobalamin [ 138 , 140 , 153 , 154 ].…”

“…Methylation of homocyteine to methionone depends on two other important vitamins, cobalamin (vitB 12 ), and folate (vitB 9 ), where PLP-dependent enzymes such as SHMT, which converts tetrahydrofolate (THF) to 5, 10-methylene tetrahydrofolate, are involved ( Figure 6 ). Elevated levels of homocysteine, otherwise known as hyperhomocysteinemia, are recognized as a cardiovascular risk factor; are a predictor of primary-cause vascular mortality; and have also been associated with mental retardation, seizures, depression, schizophrenia, and cognitive impairment [ 138 , 153 , 160 , 161 ]. Homocysteine can be converted in three different ways in the cell.…”

The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

“…TgCRND8 mice (a mouse model of AD, Table 1 1 ) on this diet show reduced DNA methyltransferase activity, hypomethylation of the Psen1 promoter, increased PSEN1 expression, and increased level of amyloid plaques ( Fuso et al, 2008 ; Fuso et al, 2011 ). Supplementing with SAM reduced expression of Psen1 and Bace1 in the TgCRND8 mice, and the development of amyloid plaques was decreased ( Fuso et al, 2012 ; Cavallaro et al, 2017 ). Together, these data provide solid support for the idea that an imbalance in one-carbon metabolism results in reduced DNA methylation at the Psen1 gene, increasing PSEN1 expression and activity, and contributes to the build-up of amyloid deposits.…”

Cerebrospinal fluid oxidative stress markers in Alzheimer's disease

“…Pathological and experimental studies suggested that oxidative stress has a pivotal role in the occurrence and progression of Alzheimer's disease (AD) and other degenerative neurological diseases 1,2 . There are two ways to measure oxidative stress in human brain in vivo.…”