The 1102-amino-acid activity-dependent neuroprotective protein (ADNP) was originally discovered by expression cloning through the immunological identification of its 8-amino-acid sequence NAPVSIPQ (NAP), constituting the smallest active neuroprotective fragment of the protein. ADNP expression is essential for brain formation and cognitive function and is dysregulated in a variety of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and schizophrenia). ADNP has been found to be mutated in autism, with an estimated prevalence of 0.17% (together, these autism cases now constitute ADNP syndrome cases) and our recent results showed somatic mutations in ADNP in Alzheimer's disease brains correlating with tauopathy. Furthermore, Adnp haploinsufficiency in mice causes an age-dependent reduction in cognitive functions coupled with tauopathy-like features such as an increased formation of tangle-like structures, defective axonal transport, and Tau hyperphosphorylation. ADNP and its derived peptides, NAP and SKIP, directly interact with end-binding proteins (EBs), which decorate plus-tips of the growing axonal cytoskeleton—microtubules (MTs). Functionally, NAP and SKIP are neuroprotective and stimulate axonal transport. Clinical trials have suggested the potential efficacy of NAP (davunetide, CP201) for improving cognitive performance/functional activities of daily living in amnestic mild cognitive impairment (aMCI) and schizophrenia patients, respectively. However, NAP was not found to be an effective treatment (though well-tolerated) for progressive supranuclear palsy (PSP) patients. Here we review the molecular mechanism of NAP activity on MTs and how NAP modulates the MT-Tau-EBs crosstalk. We offer a molecular explanation for the different protective potency of NAP in selected tauopathies (aMCI vs. PSP) expressing different ratios/pathologies of the alternatively spliced Tau mRNA and its resulting protein (aMCI expressing similar quantities of the dynamic Tau 3-MT binding isoform (Tau3R) and the Tau 4-MT binding isoform (Tau4R) and PSP enriched in Tau4R pathology). We reveal the direct effect of truncated ADNPs (resulting from de novo autism and newly discovered Alzheimer's disease-related somatic mutations) on MT dynamics. We show that the peptide SKIP affects MT dynamics and MT-Tau association. Since MT impairment is linked with neurodegenerative and neurodevelopmental conditions, the current study implicates a paucity/dysregulation of MT-interacting endogenous proteins, like ADNP, as a contributing mechanism and provides hope for NAP and SKIP as MT-modulating drug candidates.

1102 个氨基酸的活性依赖性神经保护蛋白 (ADNP) 最初是通过表达克隆通过其 8 个氨基酸序列 NAPVSIPQ (NAP) 的免疫学鉴定发现的，构成该蛋白的最小活性神经保护片段。ADNP 表达对于大脑形成和认知功能至关重要，并且在多种神经退行性疾病（阿尔茨海默病、帕金森病和精神分裂症）中失调。已发现 ADNP 在自闭症中发生突变，估计患病率为 0.17%（这些自闭症病例现在共同构成 ADNP 综合征病例），我们最近的结果显示阿尔茨海默病大脑中 ADNP 的体细胞突变与 tau 蛋白病相关。此外，Adnp小鼠单倍剂量不足会导致认知功能的年龄依赖性降低，并伴有 tau 蛋白病样特征，例如缠结样结构的形成增加、轴突运输缺陷和 Tau 过度磷酸化。ADNP 及其衍生肽 NAP 和 SKIP 直接与末端结合蛋白 (EB) 相互作用，EB 修饰正在生长的轴突细胞骨架 - 微管 (MT) 的尖端。在功能上，NAP 和 SKIP 具有神经保护作用并刺激轴突运输。临床试验表明，NAP（davunetide，CP201）分别具有改善遗忘性轻度认知障碍（aMCI）和精神分裂症患者的认知能力/日常生活功能活动的潜在功效。然而，尚未发现 NAP 是进行性核上性麻痹 (PSP) 患者的有效治疗方法（尽管耐受性良好）。在这里，我们回顾了 NAP 对 MT 活动的分子机制以及 NAP 如何调节 MT-Tau-EB 串扰。我们为 NAP 在选定的 tauopathies (aMCI) 中的不同保护效力提供了分子解释与PSP相比，表达不同比例/病理的选择性剪接 Tau mRNA 及其产生的蛋白质（aMCI 表达相似数量的动态 Tau 3-MT 结合亚型（Tau3R）和 Tau 4-MT 结合亚型（Tau4R）和 PSP 富集）在 Tau4R 病理学中）。我们揭示了截断的 ADNP（由新发自闭症和新发现的阿尔茨海默病相关体细胞突变引起）对 MT 动力学的直接影响。我们表明肽 SKIP 影响 MT 动力学和 MT-Tau 关联。由于 MT 损伤与神经退行性和神经发育状况有关，目前的研究表明，与 MT 相互作用的内源性蛋白质（如 ADNP）的缺乏/失调是一种促成机制，并为 NAP 和 SKIP 作为 MT 调节药物候选者提供了希望。