1α,25-Dihydroxyvitamin D3 Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease
1α,25-Dihydroxyvitamin D3 Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease
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DOI：
10.1523/jneurosci.2711-13.2014
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发表时间：
2014-05-21
影响因子：
5.3
通讯作者：
Pang, K. Sandy
中科院分区：
文献类型：
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作者：
Durk, Matthew R.;Han, Kyung;Pang, K. Sandy
我们证明了维生素 D 受体 (VDR) 在减少大脑可溶性和不溶性淀粉样蛋白 - β (A β 肽) 方面的作用。用 1 α,25-二羟基维生素 D-3 [1,25(OH)(2)D-3]（VDR 的内源性活性配体）对两种人类淀粉样前体蛋白表达模型 Tg2576 和 TgCRND8 小鼠进行短期治疗，导致脑 P 糖蛋白水平升高(P-gp) 和较低的可溶性 A β 水平，在斑块形成期间用 1,25(OH)(2)D-3 长期治疗 TgCRND8 小鼠，可抵消与 elacridar（一种 P-gp 抑制剂）共同给药的影响，减少可溶性和不溶性斑块相关的 A β，特别是在海马中，其中 VDR 丰富，并且在 1,25(OH)(2)D-3 治疗后 P-gp 诱导最强。在喂食缺乏维生素 D 的小鼠中，这导致了条件性恐惧记忆的改善，观察到大脑 P-gp 表达较低，但补充 VDR 配体后，其水平得以恢复。综合数据表明，VDR 是预防和治疗阿尔茨海默病的重要治疗靶点。
We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-beta (A beta peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble A beta levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH)(2)D-3 during the period of plaque formation reduced soluble and insoluble plaque-associated A beta, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH)(2)D-3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease.