Dietary Supplementation with S-Adenosyl Methionine Delayed Amyloid-β and Tau Pathology in 3xTg-AD Mice

S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimer's disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, gamma-secretase activity, and levels of amyloid-beta (A beta) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human A beta PP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for A beta and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular A beta PP/A beta and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular A beta deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses.