A Dual Mechanism Linking NGF/proNGF Imbalance and Early Inflammation to Alzheimer's Disease Neurodegeneration in the AD11 Anti-NGF Mouse Model
A Dual Mechanism Linking NGF/proNGF Imbalance and Early Inflammation to Alzheimer's Disease Neurodegeneration in the AD11 Anti-NGF Mouse Model
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DOI：
10.2174/187152711796235032
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发表时间：
2011-08-01
影响因子：
3
通讯作者：
Cattaneo, A.
中科院分区：
文献类型：
--
作者：
Capsoni, S.;Brandi, R.;Cattaneo, A.
神经营养因子神经生长因子(NGF)对基底前脑胆碱能神经元的维持和分化是必不可少的。由于基底前脑胆碱能神经元是阿尔茨海默病(AD)中受影响和进行性退行性变的一个主要神经元群体，因此NGF作为一种潜在的治疗药物在与衰老有关的神经退行性疾病中受到了越来越多的关注，尤其是对AD。然而，除了胆碱能缺陷之外，还没有证据表明NGF信号的缺陷与阿尔茨海默氏症级联反应中更广泛的激活有关。通过“神经抗体”表型蛋白敲除策略获得的AD11抗NGF转基因小鼠的表型分析，允许证明NGF缺乏和AD病理之间的直接因果联系。自那以后，对AD11模型的广泛机制研究为NGF运输和信号转导的改变在散发性阿尔茨海默病神经退行性变中发挥关键作用的概念提供了新的转折，导致了神经营养失衡假说，认为神经营养失衡是散发性AD的上游驱动因素。在AD11抗NGF小鼠身上获得的结果强调了这样一个事实，即NGF中和的特殊模式，即在大脑中表达的NGF抗体，选择性地干扰成熟的NGF而不是未加工的ProNGF，在神经退行性变的机制中发挥着重要作用，并可能为人类散发性AD的机制带来新的见解。在这里，我们将回顾(1)AD的新的神经营养失衡假说和(2)AD11抗NGF小鼠神经退行性变表型的机制。
The neurotrophin Nerve Growth Factor (NGF) is essential for the maintenance and differentiation of basal forebrain cholinergic neurons. Since basal forebrain cholinergic neurons represent one major neuronal population affected and progressively degenerating in Alzheimer's disease (AD), interest has grown for NGF as a potential therapeutic agent in neurodegenerative disorders linked to aging, particularly for AD. However, no evidence was available, to link, in a cause-effect manner, deficits in NGF signalling to the broader activation in the Alzheimer's cascade, besides cholinergic deficits. The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the "neuroantibodies" phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of "neurotrophic imbalance" as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD. Here, we will review (1) the renewed neurotrophic imbalance hypothesis for AD and (2) the mechanisms underlying the neurodegenerative phenotype of AD11 anti-NGF mice.