S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice Andrea Fuso a,b, *, Vincenzina Nicolia a , Laura Ricceri c , Rosaria A. Cavallaro a , Elisa Isopi a,d , Franco Mangia b , Maria Teresa Fiorenza b , Sigfrido Scarpa a a Department of Surgery “P. Valdoni”, Via Antonio Scarpa, 14 – 00161, Sapienza University of Rome, Italy b Department of Psychology, Section of Neuroscience, Via dei Marsi 78, 00185, Sapienza University of Rome, Italy c Section of Neurotoxicology and Neuroendocrinology, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299 – 00161, Rome, Italy d Current address: Department of Neuroscience and Imaging and Molecular Neurology Unit, Center of Excellence on Aging (CeSI), University G, d’Annunzio, Chieti, Italy Received 12 September 2011; received in revised form 5 December 2011; accepted 6 December 2011 Abstract Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer’s disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer’s disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease. © 2012 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; One-carbon metabolism; Homocysteine; S-adenosylmethionine; B vitamins; Alzheimer’s treatment 1. Introduction High plasma levels of homocysteine (hyperhomocys- teinemia, HHCY) are consistently observed in sporadic Alz- heimer’s disease (LOAD: Late Onset Alzheimer’s disease) and thus represent a topical area in AD research (Herrmann and Knapp, 2002; Miller, 2000; Quadri et al., 2005; Selhub, 2008; Van Dam and Van Gool, 2009). However, in spite of the general agreement on HHCY and LOAD Association, epidemiological studies do not clearly sustain a maker role of HHCY in LOAD onset/progression. In fact, HHCY could be a mere consequence of neurodegeneration (Selhub, 2006), epidemiological studies are clearly biased (Mc- Mahon et al., 2006 and related comments) and evidence supporting causative roles for HHCY in LOAD is still insufficient. Another major difficulty in studying mecha- nisms downstream from HHCY in LOAD is that transgenic AD models do not fully represent the sporadic form of this disease (Wilcock, 2010). Nevertheless, it was demonstrated that hyperhomocysteinemia induces amyloid deposition (Lin et al., 2009; Pacheco-Quinto et al., 2006; Zhuo et al., 2010), Tau phosphorylation (McCampbell et al., 2011; Sontag et al., 2007), microglia activation (Zou et al., 2010) * Corresponding author. Tel.: +390649766601; fax: +390649766600. E-mail address: andrea.fuso@uniroma1.it (A. Fuso). Neurobiology of Aging 33 (2012) 1482.e1–1482.e16 www.elsevier.com/locate/neuaging 0197-4580/$ – see front matter © 2012 Elsevier Inc. All rights reserved. 10.1016/j.neurobiolaging.2011.12.013