Paris Daniel, Townsend Kirk P, Obregon Demian F, Humphrey James, Mullan Michael
The Roskamp Institute, University of South Florida, Tampa 33613, USA.
Prostaglandins Other Lipid Mediat. 2002 Sep;70(1-2):1-12. doi: 10.1016/s0090-6980(02)00111-9.
It has recently been shown that the level of soluble beta-amyloid (Abeta) peptides correlates well with the severity of synaptic loss and the density of neurofibrillary tangles observed in Alzheimer's disease (AD) brain. However, the biological activity of soluble forms of Abeta peptides in the brain remains to be determined. We have investigated ex vivo the effect of freshly solubilized Abeta1-40 peptides (fsAbeta) on prostaglandin E2 (PGE2) production in rat brain slices. PGE2 levels increased rapidly following treatment with fsAbeta, an effect that was prevented by SB202190, a selective inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and by NS-398, which preferentially inhibits cyclooxygenase-2 (COX-2) compared to COX-1. In an attempt to determine the cellular systems of the brain responsible for prostaglandin production in response to fsAbeta, the effect of fsAbeta was tested on isolated brain microvessels, primary cultures of brain smooth muscle cells/pericytes and endothelial cells, and a human neuron-like cell line (IMR32). Our data show that fsAbeta ex vivo can stimulate prostaglandin accumulation in incubates of isolated rat brain microvessels. In addition, fsAbeta appears to cause a concentration-dependent enhancement of prostaglandin accumulation in primary cultures of brain microvessel-derived smooth muscle cells/pericytes but not of brain endothelial cells. Finally, fsAbeta also stimulated PGF2alpha accumulation in cultures of differentiated IMR32 cells, but to a lesser extent than in brain smooth muscle cell/pericyte cultures. Deposition of aggregated forms of Abeta in the brain has been thought to trigger an inflammatory response which accompanies the neuropathologic events of AD. Our data provide evidence that fsAbeta triggers a pro-inflammatory reaction in rat brain, and suggest that the cerebrovasculature may constitute an important source of pro-inflammatory eicosanoids.
最近研究表明，可溶性β-淀粉样蛋白（Aβ）肽水平与阿尔茨海默病（AD）脑内观察到的突触丧失严重程度及神经原纤维缠结密度密切相关。然而，脑内可溶性Aβ肽的生物学活性仍有待确定。我们已在体外研究了新溶解的Aβ1-40肽（fsAβ）对大鼠脑片前列腺素E2（PGE2）产生的影响。用fsAβ处理后，PGE2水平迅速升高，p38丝裂原活化蛋白激酶（p38 MAPK）的选择性抑制剂SB202190以及与COX-1相比优先抑制环氧化酶-2（COX-2）的NS-398可阻止这种效应。为了确定脑内负责响应fsAβ产生前列腺素的细胞系统，我们测试了fsAβ对分离的脑微血管、脑平滑肌细胞/周细胞和内皮细胞的原代培养物以及人神经元样细胞系（IMR32）的影响。我们的数据表明，体外fsAβ可刺激分离的大鼠脑微血管培养物中前列腺素的积累。此外，fsAβ似乎可导致脑微血管衍生的平滑肌细胞/周细胞原代培养物中前列腺素积累呈浓度依赖性增强，但对脑内皮细胞无此作用。最后，fsAβ也刺激了分化的IMR32细胞培养物中PGF2α的积累，但程度低于脑平滑肌细胞/周细胞培养物。脑内Aβ聚集形式的沉积被认为会引发伴随AD神经病理事件的炎症反应。我们的数据提供了证据表明fsAβ在大鼠脑中引发促炎反应，并表明脑血管系统可能是促炎类花生酸的重要来源。
