The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor.
The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor.
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DOI：
10.1093/brain/aww271
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Cattaneo A
中科院分区：
文献类型：
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作者：
Capsoni S;Malerba F;Carucci NM;Rizzi C;Criscuolo C;Origlia N;Calvello M;Viegi A;Meli G;Cattaneo A
神经生长因子（NGF）是治疗阿尔茨海默病的候选药物，但由于其疼痛诱导活性，必须在脑实质内给药。Capsoni等人开发了人无痛NGF（hNGF β），并显示鼻内给药导致阿尔茨海默病小鼠脑中广泛的生物分布，具有有效的抗淀粉样蛋白生成作用。神经生长因子是治疗阿尔茨海默病的候选药物。由于其疼痛诱导活性，在目前的临床试验中，神经生长因子通过神经外科手术局部递送到大脑中，但关于局部神经生长因子递送在减少淀粉样蛋白-β沉积中的功效的数据不可用。为了减少神经生长因子引起疼痛的副作用，从而避免局部脑注射的需要，我们开发了人无痛神经生长因子（hNGFp），其灵感来自于人遗传性疾病遗传性感觉和自主神经病变V型。hNGFp具有与野生型人神经生长因子相同的神经营养效力，但疼痛敏化活性低10倍。在这项研究中，我们首先在5xFAD小鼠模型中模拟了临床试验中使用的hNGF β的实质内递送，并发现其在减少淀粉样蛋白-β斑块负荷方面无效。相反，鼻内递送相同剂量的hNGF β，其在脑中广泛生物分布并且不诱导疼痛，显示出有效的抗淀粉样蛋白生成作用并且挽救突触可塑性和记忆缺陷。我们发现hNGF β作用于神经胶质细胞，调节炎性蛋白如可溶性TNFα受体II和趋化因子CXCL 12。我们进一步确定了hNGF β的拯救作用是由CXCL 12介导的，因为CXCL 12受体CXCR 4的药理学抑制阻断了大多数hNGF β作用。这些发现具有重要的治疗意义：（i）我们确定了神经生长因子充分发挥其神经保护作用所需的大脑广泛暴露;以及（ii）我们已经确定了一种新的抗神经退行性通路作为神经退行性疾病新治疗机会的广泛靶点。
Nerve growth factor (NGF) is a therapeutic candidate for Alzheimer’s disease, but must be administered intraparenchymally owing to its pain-inducing activity. Capsoni et al. develop human painless NGF (hNGFp) and show that intranasal administration results in widespread biodistribution in the brains of Alzheimer’s disease mice, with potent anti-amyloidogenic effects. Nerve growth factor is a therapeutic candidate for Alzheimer’s disease. Due to its pain-inducing activity, in current clinical trials nerve growth factor is delivered locally into the brain by neurosurgery, but data on the efficacy of local nerve growth factor delivery in decreasing amyloid-β deposition are not available. To reduce the nerve growth factor pain-inducing side effects, thus avoiding the need for local brain injection, we developed human painless nerve growth factor (hNGFp), inspired by the human genetic disease hereditary sensory and autonomic neuropathy type V. hNGFp has identical neurotrophic potency as wild-type human nerve growth factor, but a 10-fold lower pain sensitizing activity. In this study we first mimicked, in the 5xFAD mouse model, the intraparenchymal delivery of hNGFp used in clinical trials and found it to be ineffective in decreasing amyloid-β plaque load. On the contrary, the same dose of hNGFp delivered intranasally, which was widely biodistributed in the brain and did not induce pain, showed a potent anti-amyloidogenic action and rescued synaptic plasticity and memory deficits. We found that hNGFp acts on glial cells, modulating inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. We further established that the rescuing effect by hNGFp is mediated by CXCL12, as pharmacological inhibition of CXCL12 receptor CXCR4 occludes most of hNGFp effects. These findings have significant therapeutic implications: (i) we established that a widespread exposure of the brain is required for nerve growth factor to fully exert its neuroprotective actions; and (ii) we have identified a new anti-neurodegenerative pathway as a broad target for new therapeutic opportunities for neurodegenerative diseases.