Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
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DOI：
10.1523/jneurosci.2441-08.2008
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发表时间：
2008-10-22
期刊：
影响因子：
--
通讯作者：
Lamb BT
中科院分区：
文献类型：
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作者：
Varvel NH;Bhaskar K;Patil AR;Pimplikar SW;Herrup K;Lamb BT
在阿尔茨海默病（AD）中经历变性的神经元甚至在实质性AD脑病理学发展之前就表现出重新进入有丝分裂细胞周期的证据。在努力确定这些细胞周期事件（CCE）的启动因素，我们的特点是出现在基因组为基础的R1.40转基因小鼠模型的AD的神经元CCE。值得注意的是，R1.40小鼠表现出可再现的时间和空间模式的神经元CCE，重现了在人类AD中观察到的神经元脆弱性。神经元CCE在6个月时首次出现在额叶皮质层II/III中。这是可检测到的淀粉样β（Aβ）沉积前6-8个月，表明特定的淀粉样前体蛋白（APP）加工产物负责诱导神经元CCE。此外，Aβ水平的降低（通过将遗传背景从C57 BL/6转移到DBA/2小鼠品系来实现）显著延迟了神经元CCE的出现。更重要的是，β-分泌酶活性的消除阻断了CCE的出现，提供了直接的遗传证据，表明APP的淀粉样蛋白形成加工是诱导CCE所必需的。最后，在体外制备的寡聚体（而非单体）Aβ可诱导分离的皮质神经元的DNA合成，这种反应可被抗寡聚体特异性抗体阻断。总之，我们的数据表明，Aβ的低分子量聚集体诱导阿尔茨海默病小鼠模型的神经元细胞周期重新进入。
Neurons subject to degeneration in Alzheimer’s disease (AD) exhibit evidence of re-entry into a mitotic cell cycle even before the development of substantial AD brain pathology. In efforts to identify the initiating factors underlying these cell cycle events (CCEs), we have characterized the appearance of the neuronal CCEs in the genomic-based R1.40 transgenic mouse model of AD. Notably, R1.40 mice exhibit neuronal CCEs in a reproducible temporal and spatial pattern that recapitulates the neuronal vulnerability seen in human AD. Neuronal CCEs first appear at 6 months in the frontal cortex layers II/III. This is 6–8 months before detectable amyloid β (Aβ) deposition, suggesting that specific amyloid precursor protein (APP) processing products are responsible for the induction of neuronal CCEs. Furthermore, a reduction in the levels of Aβ (achieved by shifting the genetic background from C57BL/6 to the DBA/2 mouse strain) dramatically delays the appearance of neuronal CCEs. More significantly, elimination of β-secretase activity blocks the appearance of CCEs, providing direct genetic evidence that the amyloidogenic processing of APP is required for the induction of CCEs. Finally, in vitro preparations of oligomeric, but not monomeric,Aβ induce DNA synthesis in dissociated cortical neurons, and this response is blocked by antioligomer specific antibodies. Together, our data suggest that low molecular weight aggregates of Aβ induce neuronal cell cycle re-entry in mouse models of Alzheimer’s disease.