Folic acid potentiates the effect of memantine on spatial learning and neuronal protection in an alzheimer's disease transgenic model

Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-β (Aβ) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Aβ accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)-M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)-M (both p < 0.05). Analysis of Aβ{40} and Aβ{42} showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)-M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)-M (p< 0.005). DNA analysis revealed that in the Tg(+)M-+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)-M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Aβ production, and modification of brain gene expression.