Balcells Mercedes, Wallins Joseph S, Edelman Elazer R
Harvard-MIT Division of Health Sciences and Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
Neurosci Lett. 2008 Aug 29;441(3):319-22. doi: 10.1016/j.neulet.2008.06.061. Epub 2008 Jun 27.
Amyloid beta (Abeta), a peptide family produced and deposited in neurons and endothelial cells (EC), is found at subnanomolar concentrations in the plasma of healthy individuals. Simple conformational changes produce a form of Abeta, Abeta42, which creates toxic plaque in the brains of Alzheimer's patients. Oxidative stress induced blood brain barrier degeneration has been proposed as a key factor for Abeta42 toxicity, but cannot account for lack of injury from the same peptide in healthy tissues. We hypothesized that cell state mediates Abeta effect. Thus, we examined the viability of aortic EC, vascular smooth muscle cells (SMC) and epithelial cells (EPI) in different states in the presence of Abeta secreted from transfected Chinese hamster ovary cells (CHO). Abeta was more toxic to all cell types when they were subconfluent. Subconfluent EC sprouted and SMC and EPI were inhibited by Abeta. Confluent EC were virtually resistant to Abeta and suppressed Abeta production by Abeta+CHO. Products of subconfluent EC overcame this resistant state, stimulating the production and toxicity of Abeta42. Confluent EC overgrew approximately 35% beyond their quiescent state in the presence of Abeta conditioned in media from subconfluent EC. These findings imply that Abeta42 may well be even more cytotoxic to cells in injured or growth states and potentially explain the variable and potent effects of this protein. One may now need to consider tissue and cell state in addition to local concentration of and exposure duration to Abeta. The specific interactions of Abeta and EC in a state-dependent fashion may help understand further the common and divergent forms of vascular and cerebral toxicity of Abeta and the spectrum of AD.
淀粉样β蛋白（Aβ）是一类在神经元和内皮细胞（EC）中产生并沉积的肽家族，在健康个体的血浆中以亚纳摩尔浓度存在。简单的构象变化会产生一种Aβ形式，即Aβ42，它会在阿尔茨海默病患者的大脑中形成有毒斑块。氧化应激诱导的血脑屏障退化被认为是Aβ42毒性的关键因素，但无法解释同一肽在健康组织中为何没有造成损伤。我们假设细胞状态介导了Aβ的作用。因此，我们检测了在转染的中国仓鼠卵巢细胞（CHO）分泌的Aβ存在下，不同状态的主动脉EC、血管平滑肌细胞（SMC）和上皮细胞（EPI）的活力。当所有细胞类型处于亚汇合状态时，Aβ对它们的毒性更大。亚汇合的EC会发芽，而SMC和EPI会受到Aβ的抑制。汇合的EC对Aβ几乎具有抗性，并抑制Aβ+CHO产生Aβ。亚汇合EC的产物克服了这种抗性状态，刺激了Aβ42的产生和毒性。在存在来自亚汇合EC的培养基中培养的Aβ的情况下，汇合的EC比其静止状态生长超过了约35%。这些发现表明，Aβ42对处于损伤或生长状态的细胞可能具有更强的细胞毒性，并可能解释这种蛋白质的可变和强效作用。现在人们可能需要除了考虑Aβ的局部浓度和暴露持续时间外，还要考虑组织和细胞状态。Aβ与EC以状态依赖方式的特异性相互作用可能有助于进一步理解Aβ血管毒性和脑毒性的共同和不同形式以及阿尔茨海默病的范围。
