Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-β and is overexpressed in dystrophic neurites in Alzheimer's brain
Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-β and is overexpressed in dystrophic neurites in Alzheimer's brain
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DOI：
10.1523/jneurosci.0575-06.2006
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发表时间：
2006-12-06
影响因子：
5.3
通讯作者：
Trullas, Ramon
中科院分区：
文献类型：
--
作者：
Abad, Maria A.;Enguita, Marta;Trullas, Ramon
淀粉样蛋白-β（A β）的积累被认为在突触的进行性丧失、神经突损伤和神经元死亡中起核心作用，这些是受阿尔茨海默病影响的大脑中的特征。然而，A β产生这种神经毒性的机制仍不清楚。由于A β抑制突触活性，我们研究了A β的神经毒性是否依赖于NP 1的表达，NP 1是一种参与兴奋性突触重塑的蛋白质，最近已被证明介导成熟神经元中神经元活性降低诱导的神经元死亡。我们发现，A β处理培养的皮层神经元，在神经细胞凋亡毒性之前，NP 1蛋白显著增加。通过RNA干扰（RNA干扰的短发夹RNA）沉默NP 1基因表达可防止突触丢失、轴突生长减少和A β诱导的细胞凋亡。NP 1的转基因过表达再现了A β的这些神经毒性作用。此外，我们发现，NP 1增加，在营养不良的神经突起的大脑患者散发晚发性阿尔茨海默氏病。NP 1和tau的双重免疫组化显示NP 1与营养不良神经突中的tau沉积物共定位。此外，NP 1与SNAP-25（25 kDa的突触体相关蛋白）共定位在大多数淀粉样沉积物周围的营养不良性神经突中。在APP/PS1（突变淀粉样前体蛋白/早老素1）转基因小鼠的大脑皮层和海马中淀粉样斑块周围的细胞过程中，NP 1也增加。这些发现表明，NP 1是A β诱发的突触丢失、神经突损伤和凋亡性神经元死亡的关键因素，并表明A β通过调节NP 1表达而促成阿尔茨海默病的病理学。
Accumulation of amyloid-beta(A beta) is thought to play a central role in the progressive loss of synapses, the neurite damage, and the neuronal death that are characteristic in brains affected by Alzheimer's disease. However, the mechanisms through which A beta produces such neurotoxicity remain unclear. Because A beta depresses synaptic activity, we investigated whether the neurotoxicity of A beta depends on the expression of NP1, a protein involved in excitatory synapse remodeling that has recently been shown to mediate neuronal death induced by reduction in neuronal activity in mature neurons. We found that treatment of cortical neurons in culture with A beta produces a marked increase in NP1 protein that precedes apoptotic neurotoxicity. Silencing NP1 gene expression by RNA interference ( short hairpin RNA for RNA interference) prevents the loss of synapses, the reduction in neurite outgrowth, and the apoptosis evoked by A beta. Transgene overexpression of NP1 reproduced these neurotoxic effects of A beta. Moreover, we found that NP1 was increased in dystrophic neurites of brains from patients with sporadic late-onset Alzheimer's disease. Dual immunohistochemistry for NP1 and tau showed that NP1 colocalizes with tau deposits in dystrophic neurites. Furthermore, NP1 colocalized with SNAP-25 (synaptosomal-associated protein of 25 kDa) in the majority of dystrophic neurites surrounding amyloid deposits. NP1 was also increased in cell processes surrounding amyloid plaques in the cerebral cortex and hippocampus of APP/PS1 ( mutant amyloid precursor protein/presenilin 1) transgenic mice. These findings show that NP1 is a key factor for the synapse loss, the neurite damage, and the apoptotic neuronal death evoked by A beta and indicate that A beta contributes to the pathology of Alzheimer's disease by regulating NP1 expression.