Affiliations: [a] Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan | [b] Department of Nutritional Science, Fu-Jen Catholic University, Taipei County, Taiwan | [c] Department of Pathology, Taipei Medical University Hospital, Taiwan | [d] Department of Medicine, Fu-Jen Catholic University, Taipei County, Taiwan | [e] Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan
Correspondence:
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Correspondence to: Dr. Ming-Jang Chiu, Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan S. Rd., Taipei, 100, Taiwan. Tel.: +886 933929393; Fax: +886 2 23418395; E-mail: [email protected].
Abstract: 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 Aβ40 and Aβ42 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.
