Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein.
Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein.
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DOI：
10.1016/j.mcn.2013.07.003
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发表时间：
2013-09
影响因子：
3.5
通讯作者：
Schinder, Alejandro F.
中科院分区：
文献类型：
--
作者：
Morgenstern, Nicolas A.;Giacomini, Damiana;Lombardi, Gabriela;Castano, Eduardo M.;Schinder, Alejandro F.
神经元连接和突触重塑是高级脑功能的基本基质。了解它们在哺乳动物异体皮质中的动态是解决正常衰老和神经退行性疾病中认知下降的细胞基础的关键一步。在这项工作中，我们设计了一种新的方法来评估由人类淀粉样前体蛋白（hAPP）的慢性细胞自主过度表达引起的功能和结构连接的动态变化。我们已经利用海马不断产生新的齿状颗粒细胞（GC）的事实来探测在健康背景中表达不同hAPP变体的GC的形态功能发育。通过逆转录病毒递送，hAPP与荧光报告基因一起在幼年小鼠齿状回的神经祖细胞中表达。在感染后几天（dpi）分析神经元后代。hAPP的淀粉样蛋白生成裂解产物如β-C末端片段（β-CTF）在21 dpi时诱导突触能连接的显著减少，此时新的GC经历活跃的生长和突触发生。有趣的是，这种效应是短暂的，因为到35 dpi时，脑电输入的强度是正常的。树突长度的减少，棘密度没有变化，与突触形成没有改变的树突发育延长一致，这延迟了突触发生。最后，通过过度表达α-CTF（hAPP的非淀粉样蛋白裂解产物），观察到新生儿GC发育中的类似缺陷。这些结果表明，hAPP可以独立于淀粉样蛋白加工途径引起延长的树突发育。
Neuronal connectivity and synaptic remodeling are fundamental substrates for higher brain functions. Understanding their dynamics in the mammalian allocortex emerges as a critical step to tackle the cellular basis of cognitive decline that occurs during normal aging and in neurodegenerative disorders. In this work we have designed a novel approach to assess alterations in the dynamics of functional and structural connectivity elicited by chronic cell-autonomous overexpression of the human amyloid precursor protein (hAPP). We have taken advantage of the fact that the hippocampus continuously generates new dentate granule cells (GCs) to probe morphofunctional development of GCs expressing different variants of hAPP in a healthy background. hAPP was expressed together with a fluorescent reporter in neural progenitor cells of the dentate gyrus of juvenile mice by retroviral delivery. Neuronal progeny was analyzed several days post infection (dpi). Amyloidogenic cleavage products of hAPP such as the β-C terminal fragment (β-CTF) induced a substantial reduction in glutamatergic connectivity at 21 dpi, at which time new GCs undergo active growth and synaptogenesis. Interestingly, this effect was transient, since the strength of glutamatergic inputs was normal by 35 dpi. This delay in glutamatergic synaptogenesis was paralleled by a decrease in dendritic length with no changes in spine density, consistent with a protracted dendritic development without alterations in synapse formation. Finally, similar defects in newborn GC development were observed by overexpression of α-CTF, a non-amyloidogenic cleavage product of hAPP. These results indicate that hAPP can elicit protracted dendritic development independently of the amyloidogenic processing pathway.
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影响因子：
3.7
作者：
Mongiat LA;Espósito MS;Lombardi G;Schinder AF
通讯作者：
Schinder AF
影响因子：
9.8
作者：
Dupret D;Fabre A;Döbrössy MD;Panatier A;Rodríguez JJ;Lamarque S;Lemaire V;Oliet SH;Piazza PV;Abrous DN
通讯作者：
Abrous DN
影响因子：
16.2
作者：
Kamenetz, F;Tomita, T;Malinow, R
通讯作者：
Malinow, R
DOI：
10.1126/science.1214956
发表时间：
2012-03-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Marín-Burgin A;Mongiat LA;Pardi MB;Schinder AF
通讯作者：
Schinder AF
影响因子：
2.5
作者：
Dayer, AG;Ford, AA;Cameron, HA
通讯作者：
Cameron, HA