Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines.
Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines.
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DOI：
10.1016/j.neuroscience.2010.04.078
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发表时间：
2010-08-11
期刊：
影响因子：
3.3
通讯作者：
Hoe, H. S.
中科院分区：
文献类型：
--
作者：
Lee, K. J.;Moussa, C. E. H.;Lee, Y.;Sung, Y.;Howell, B. W.;Turner, R. S.;Pak, D. T. S.;Hoe, H. S.
β淀粉样蛋白（Aβ）诱导的突触丢失被认为是阿尔茨海默病认知能力下降的主要原因。Aβ是由淀粉样前体蛋白（APP）的蛋白水解产生的，APP是一种突触受体，其生理功能尚不清楚。在本研究中，我们研究了APP在树突棘形成中的作用，这对学习和记忆很重要。我们发现APP的过度表达增加了海马神经元的棘数，而APP的敲低降低了海马神经元的棘密度。APP的这种促刺作用需要APP的细胞外和细胞内结构域，并且伴随着AMPA受体亚基GluR 2而不是GluR 1的特异性上调。在体内实验中，我们发现，皮质层II/III和海马CA 1区锥体神经元在1岁APP缺陷小鼠比野生型同窝仔有更少和更短的树突棘。相反，过表达突变APP的转基因小鼠与对照动物相比，脊柱密度增加，尽管只是在可溶性淀粉样蛋白过度积累之前的年轻时期。此外，在年轻的APP转基因小鼠大脑中观察到谷氨酸合成增加，而在APP缺陷小鼠中谷氨酸水平降低，GABA水平增加。这些结果表明APP对于促进脊柱形成是重要的，并且是脊柱正常发育所必需的。
Synapse loss induced by amyloid beta (Aβ) is thought to be a primary contributor to cognitive decline in Alzheimer’s disease. Aβ is generated by proteolysis of amyloid precursor protein (APP), a synaptic receptor whose physiological function remains unclear. In the present study, we investigated the role of APP in dendritic spine formation, which is known to be important for learning and memory. We found that overexpression of APP increased spine number, whereas knockdown of APP reduced spine density in cultured hippocampal neurons. This spine-promoting effect of APP required both the extracellular and intracellular domains of APP, and was accompanied by specific upregulation of the GluR2, but not the GluR1, subunit of AMPA receptors. In an in vivo experiment, we found that cortical layers II/III and hippocampal CA1 pyramidal neurons in 1 year-old APP-deficient mice had fewer and shorter dendritic spines than wild-type littermates. In contrast, transgenic mice overexpressing mutant APP exhibited increased spine density compared to control animals, though only at a young age prior to overaccumulation of soluble amyloid. Additionally, increased glutamate synthesis was observed in young APP transgenic brains, whereas glutamate levels were decreased and GABA levels were increased in APP-deficient mice. These results demonstrate that APP is important for promoting spine formation and is required for proper spine development.
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影响因子：
4.8
作者：
Hoe, Hyang-Sook;Minami, S. Sakura;Rebeck, G. William
通讯作者：
Rebeck, G. William
DOI：
10.1111/j.1749-6632.1993.tb17246.x
发表时间：
1993-01-01
期刊：
BRAIN MECHANISMS
影响因子：
--
作者：
LEDOUX, JE
通讯作者：
LEDOUX, JE
影响因子：
5.3
作者：
Hoe, Hyang-Sook;Cooper, Matthew J.;Rebeck, G. William
通讯作者：
Rebeck, G. William
影响因子：
5.3
作者：
Priller, Christina;Bauer, Thomas;Herms, Jochen
通讯作者：
Herms, Jochen
影响因子：
64.8
作者：
Passafaro, M;Nakagawa, T;Sheng, M
通讯作者：
Sheng, M