Capsoni Simona, Malerba Francesca, Carucci Nicola Maria, Rizzi Caterina, Criscuolo Chiara, Origlia Nicola, Calvello Mariantonietta, Viegi Alessandro, Meli Giovanni, Cattaneo Antonino
1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.
2 Institute of Neuroscience, National Council for Research, Pisa, Italy.
Brain. 2017 Jan;140(1):201-217. doi: 10.1093/brain/aww271.
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.
神经生长因子是治疗阿尔茨海默病的候选药物。由于其具有诱发疼痛的活性，在当前的临床试验中，神经生长因子通过神经外科手术局部注入大脑，但关于局部递送神经生长因子减少淀粉样β蛋白沉积疗效的数据尚不可得。为了减少神经生长因子诱发疼痛的副作用，从而避免局部脑内注射的需要，我们受人类遗传性感觉和自主神经病变Ⅴ型启发，开发了人无痛神经生长因子（hNGFp）。hNGFp具有与野生型人神经生长因子相同的神经营养效力，但疼痛致敏活性低10倍。在本研究中，我们首先在5xFAD小鼠模型中模拟了临床试验中使用的hNGFp实质内递送，发现其在减少淀粉样β斑块负荷方面无效。相反，相同剂量的hNGFp经鼻递送，可在脑内广泛分布且不诱发疼痛，显示出强大的抗淀粉样蛋白生成作用，并挽救了突触可塑性和记忆缺陷。我们发现hNGFp作用于神经胶质细胞，调节可溶性TNFα受体II和趋化因子CXCL12等炎症蛋白。我们进一步确定，hNGFp的挽救作用是由CXCL12介导的，因为对CXCL12受体CXCR4的药理学抑制阻断了hNGFp的大部分作用。这些发现具有重要的治疗意义：（i）我们确定神经生长因子要充分发挥其神经保护作用需要大脑广泛暴露；（ii）我们确定了一条新的抗神经退行性途径，作为神经退行性疾病新治疗机会的广泛靶点。
