Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model
Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model
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DOI：
10.1016/j.neuron.2004.08.013
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发表时间：
2004-09-02
期刊：
影响因子：
16.2
通讯作者：
Cole, GM
中科院分区：
文献类型：
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作者：
Calon, F;Lim, GP;Cole, GM
学习和记忆依赖于树突脊柱肌动蛋白组装和二十二碳六烯酸（DHA），一种必需的n-3 （omega-3）多不饱和脂肪酸（PFA）。高DHA摄入与降低阿尔茨海默病（AD）风险有关，但机制和治疗潜力仍不明确。在这里，我们报告了在AD小鼠模型中，饮食中n-3 PFA的减少导致80%-90%的磷脂酰肌醇3-激酶p85 α亚基和突触后肌动蛋白调节蛋白drebrin的损失，就像在AD大脑中一样。突触后蛋白的丢失与氧化增加有关，没有伴随神经元或突触前蛋白的丢失。N-3 PFA缺失增加了caspase切割的肌动蛋白，其在超微结构上定位于树突。用DHA治疗n-3 pfa限制小鼠可以防止这些影响和行为缺陷，并增加抗凋亡BAD磷酸化。由于n-3 PFAs对于p85介导的中枢神经系统胰岛素信号传导和突触后蛋白的选择性保护至关重要，因此这些发现对突触丧失至关重要的神经退行性疾病，特别是阿尔茨海默病具有重要意义。
Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. N-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.