Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model
Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model
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DOI：
10.1523/jneurosci.3153-08.2008
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发表时间：
2008-11-05
影响因子：
5.3
通讯作者：
Fan, Guo-Huang
中科院分区：
文献类型：
--
作者：
Ding, Yun;Qiao, Aimin;Fan, Guo-Huang
最近的研究表明，在阿尔茨海默病 (AD) 中观察到的维生素 A 信号传导中断会导致啮齿动物中 β-淀粉样蛋白 (Aβ) 的积累和记忆缺陷。本研究的目的是评估全反式视黄酸（ATRA）（一种维生素 A 的活性代谢物）对淀粉样前体蛋白（APP）和早老素 1（PS1）双转基因小鼠（一种成熟的 AD 小鼠模型）的神经病理学和空间学习和记忆缺陷的治疗效果。在这里，我们报告了在 APP/ PS1 转基因小鼠腹腔注射 ATRA（20 mg/kg，每周 3 次，在小鼠 5 个月大时开始）治疗 8 周的盲法研究中，大脑 Aβ 沉积和 tau 磷酸化显着减少。这伴随着 APP 磷酸化和加工的显着减少。细胞周期蛋白依赖性激酶 5 是参与 APP 和 tau 磷酸化的主要激酶，ATRA 治疗显着下调其活性。与媒介物处理的 APP/ PS1 小鼠相比，ATRA 处理的 APP/ PS1 小鼠表现出小胶质细胞和星形胶质细胞的活化减少，神经元变性减轻，空间学习和记忆得到改善。这些结果支持 ATRA 作为预防和治疗 AD 的有效治疗剂。
Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to beta-amyloid (A beta) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A beta deposition and tau phosphorylation in the blinded study of APP/ PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/ PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.