Chauhan Neelima B
Research and Development (151), Jesse Brown VA Medical Center Chicago, Chicago, Illinois 60612, USA.
J Neurosci Res. 2007 Feb 1;85(2):451-63. doi: 10.1002/jnr.21110.
Based on the central dogma of beta-amyloid (Abeta) as a key seeding event in the pathogenesis of Alzheimer disease (AD), immunoneutralization strategies have been actively pursued both in AD and in models of AD as a potential means for treating AD. Both active and passive immunizations targeted at fibrillar Abeta successfully remove cerebral plaque load and attenuate Abeta-induced toxicity. Consistently with this, intracerebroventricular (ICV) passive immunization established in our laboratory using antibody against fibrillar Abeta (anti-fAbeta) reduced cerebral plaque load and reversed early synaptic deficits at pre/early plaque stage when there is an abundance of soluble dimeric/oligomeric Abeta but sparse fibrillar Abeta, indicating that anti-fAbeta-mediated partial neutralization of toxic oligomeric Abeta species might have reduced early synaptotoxicity. In the previous investigation, we found that immunoneutralization with anti-fAbeta transiently reduced cerebral Abeta and associated toxicity. The current investigation tested whether ICV im munization using antibody to conformationally changed oligomeric Abeta (anti-oligoAbeta) will overcome the transient restorative nature of anti-fAbeta and produce persistent, long-lasting preventive effects. Because oligomeric Abeta is strongly correlated with synaptotoxicity, we investigated whether immunoneutralization of oligomeric Abeta will reverse synaptic deficits by analyzing presynaptic molecular marker (SNAP-25) profile within hippocampal dendritic fields, where SNAP-25 is abundantly expressed. Results show that, in contrast to ICV anti-fAbeta antibody, ICV anti-oligoAbeta antibody significantly prevented cerebral Abeta build and almost completely restored SNAP-25 immunoreaction up to 8 weeks postinjection in TgCRND8 brain. Results show that ICV passive immunization with anti-oligoAbeta antibody might be an improved ICV immunization strategy for preventing permanent structural damage in AD.
基于β-淀粉样蛋白（Aβ）作为阿尔茨海默病（AD）发病机制中的关键种子事件的中心法则，免疫中和策略在AD及其模型中一直被积极探索，作为治疗AD的一种潜在手段。针对纤维状Aβ的主动和被动免疫均成功降低了脑内斑块负荷并减轻了Aβ诱导的毒性。与此一致的是，我们实验室使用抗纤维状Aβ抗体（抗fAβ）建立的脑室内（ICV）被动免疫在斑块前期/早期阶段减少了脑内斑块负荷并逆转了早期突触缺陷，此时存在大量可溶性二聚体/寡聚体Aβ但纤维状Aβ稀少，这表明抗fAβ介导的对有毒寡聚体Aβ物种的部分中和可能降低了早期突触毒性。在先前的研究中，我们发现用抗fAβ进行免疫中和可短暂降低脑内Aβ及其相关毒性。当前的研究测试了使用针对构象改变的寡聚体Aβ抗体（抗寡聚体Aβ）进行ICV免疫是否会克服抗fAβ的短暂恢复特性并产生持久的预防效果。由于寡聚体Aβ与突触毒性密切相关，我们通过分析海马树突状区域内丰富表达突触小体相关蛋白25（SNAP-25）的突触前分子标志物谱，研究了寡聚体Aβ的免疫中和是否会逆转突触缺陷。结果表明，与ICV抗fAβ抗体不同，ICV抗寡聚体Aβ抗体显著阻止了脑内Aβ的积累，并且在TgCRND8脑内注射后长达8周几乎完全恢复了SNAP-25免疫反应。结果表明，用抗寡聚体Aβ抗体进行ICV被动免疫可能是一种改进的ICV免疫策略，用于预防AD中的永久性结构损伤。
