European Brain Research Institute, Roma, Italy.
J Alzheimers Dis. 2010;20(2):527-46. doi: 10.3233/JAD-2010-091357.
We previously showed that anti-nerve growth factor (NGF) antibodies expressed in transgenic mice (AD11) elicit a progressive neurodegeneration, comprising the triad of Alzheimer's disease (AD) hallmarks: cholinergic loss, tau hyperphosphorylation, and amyloid-beta peptide formation. However, since anti-NGF antibodies are produced both in the brain and in peripheral tissues of AD11 mice, the contribution of peripheral neutralization of NGF to the onset of brain neurodegeneration was still unexplored. To address this question, we characterized a line of transgenic mice (AD10) in which anti-NGF antibodies are obligatorily produced only in lymphocytes, being initially found in blood. In AD10 mice, peripheral NGF neutralization elicits shrinkage of superior cervical ganglia (immunosympathectomy) and, as a consequence of this, peripheral anti-NGF antibodies cross the blood brain barrier (BBB) and reach the brain, generating an NGF-dependent neurodegeneration, largely superimposable to that observed in AD11 mice. This demonstrates that peripherally originated anti-NGF antibodies can generate a neurodegeneration in the central nervous system of an animal model. Consistently, peripherally-delivered NGF is effective in preventing the onset of the central cholinergic deficit. These findings could have a direct relevance for some human sporadic AD cases, highlighting the role of the BBB disruption and suggesting a causally relevant role of circulating antibodies in AD pathology.
我们之前曾表明，在转基因小鼠（AD11）中表达的抗神经生长因子（NGF）抗体引发进行性神经退行性变，包括阿尔茨海默病（AD）的三联征：胆碱能丧失、tau 过度磷酸化和淀粉样β肽形成。然而，由于抗 NGF 抗体不仅在 AD11 小鼠的大脑中产生，而且在外周组织中产生，因此外周中和 NGF 对大脑神经退行性变的发生的贡献仍未得到探索。为了解决这个问题，我们对一种转基因小鼠（AD10）进行了特征描述，其中抗 NGF 抗体仅在淋巴细胞中强制性产生，最初在血液中发现。在 AD10 小鼠中，外周 NGF 的中和会引起颈上神经节的收缩（免疫性交感神经切除术），并且由于这种情况，外周抗 NGF 抗体穿过血脑屏障（BBB）并到达大脑，产生依赖 NGF 的神经退行性变，与在 AD11 小鼠中观察到的情况大致相同。这表明外周起源的抗 NGF 抗体可以在动物模型的中枢神经系统中产生神经退行性变。一致地，外周给予的 NGF 可有效预防中枢胆碱能不足的发生。这些发现可能与某些人类散发性 AD 病例具有直接相关性，突出了 BBB 破坏的作用，并提示循环抗体在 AD 病理学中具有因果相关作用。
