期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 20, 期 2, 页码 607-615出版社
IOS PRESS
DOI: 10.3233/JAD-2010-1396
关键词
Alzheimer's disease; folic acid; memantine; neuron protection; spatial learning; transgenic mice
资金
- NTUH [NTUH 95-S433]
Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-beta (A beta) 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 A beta 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 A beta(40) and A beta(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 A beta production, and modification of brain gene expression.
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