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

Rosaria Cavallaro,Andrea Fuso,Maria Fiorenza,Sigfrido Scarpa,Vincenzina Nicolia

doi:10.3390/antiox6040076

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.

Highlights

Alzheimer’s disease (AD) is the most common age-associated progressive neurodegenerative disorder accounting for approximately 30 million people suffering worldwide; due to demographic changes and the longer life expectancy, this number is foreseen to increase up to 115 million cases in 2050 [1,2,3,4].Most of the AD cases are sporadic, characterized by late onset (LOAD, Late Onset AD) and slow progression
The mechanisms underlying the beneficial effect of exogenous superoxide dismutase (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
To verify that exogenous SOD administration effectively improved endogenous SOD activity, enzymatic tests were performed in erythrocytes and in brain tissue of 129Sv wild type (WT) mice

Summary

Introduction

Alzheimer’s disease (AD) is the most common age-associated progressive neurodegenerative disorder accounting for approximately 30 million people suffering worldwide; due to demographic changes and the longer life expectancy, this number is foreseen to increase up to 115 million cases in 2050 [1,2,3,4].Most of the AD cases are sporadic, characterized by late onset (LOAD, Late Onset AD) and slow progression. LOAD was recently described as a multifactorial disease likely resulting from the interaction between genetic, epigenetic and environmental factors able to shift physiological aging toward pathological processes [5,7,8]. These inducing factors include diet, nutritional lifestyle, hyperhomocysteinemia and oxidative stress, which is known to play a key role in the pathogenesis of LOAD, since it is thought to be one of the earliest events in the disease [9,10,11,12,13]. Markers of oxidative damage including extensive lipid peroxidation, high levels of oxidized proteins, oxidative modifications in RNA and nuclear and mitochondrial DNA, aldehydes, were found in the blood, in cerebrospinal fluid (CSF) and post mortem brains of neurological patients with preclinical or early stage AD [3,16,17,18,19,20]

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