Department of Human Molecular Genetics and Biochemistry, School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Curr Pharm Des. 2011;17(31):3413-7. doi: 10.2174/138161211798072553.
This review focuses on the discovery of activity-dependent neuroprotective protein (ADNP) and the ensuing discovery of NAP (davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration. NAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (davunetide) interacted with microtubules, protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo. NAP (davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity and synapse formation by increasing synaptophysin expression. NAP (davunetide) protection against neurodegeneration has recently been shown to extend to katanin-related microtubule disruption under conditions of tau deficiencies. In conclusion, NAP (davunetide) provided potent neuroprotection in a broad range of neurodegenerative models, protecting the neuroglial cytoskeleton in vitro and inhibiting tau pathology (tauopathy) in vivo. Based on these extensive preclinical results, davunetide (NAP) is now being evaluated in a Phase II/III study of the tauopathy, progressive supranuclear palsy (PSP); (Allon Therapeutics Inc.).
本文重点介绍活性依赖性神保护蛋白（ADNP）的发现，以及随后针对微管保护作用的向临床开发的 NAP（达文西肽）的发现。ADNP 免疫反应性偶尔会装饰微管，ADNP 沉默抑制神经突生长，如微管相关蛋白 2（MAP2）标记所示。ADNP 敲除是致命的，而 ADNP 减少 50%（ADNP 杂合不足）导致微管相关蛋白 tau 病理与认知功能障碍和神经退行性变相关。NAP（达文西肽），一种源自 ADNP 的 8 个氨基酸肽，部分改善了与 ADNP 缺乏相关的缺陷。NAP（达文西肽）与微管相互作用，体外保护微管免受锌、诺考达唑和氧化应激相关的毒性，体内保护 tau 病理和 MAP6（稳定的仅微管多肽-STOP）病理。NAP（达文西肽）提供神经营养功能，促进神经突生长，如 MAP2 免疫反应性增加和突触形成增加突触小体蛋白表达。NAP（达文西肽）对神经退行性变的保护作用最近已被证明可扩展到 tau 缺乏条件下与katanin 相关的微管破坏。总之，NAP（达文西肽）在广泛的神经退行性模型中提供了强大的神经保护作用，在体外保护神经胶质细胞骨架，抑制体内 tau 病理（tauopathy）。基于这些广泛的临床前结果，达文西肽（NAP）现在正在 tauopathy、进行性核上性麻痹（PSP）的 II/III 期研究中进行评估；（Allon Therapeutics Inc.）。
