Gozes Illana, Iram Tal, Maryanovsky Evgenia, Arviv Carmit, Rozenberg Liora, Schirer Yulie, Giladi Eliezer, Furman-Assaf Sharon
The Adams Super Center for Brain Studies and Sagol School of Neuroscience; The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Dr. Diana and Zelman Elton (Elbaum) Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
J Alzheimers Dis. 2014;40 Suppl 1:S23-36. doi: 10.3233/JAD-131664.
NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest.
NAP(NAPVSIPQ,达武奈肽)是一种微管稳定肽类候选药物。在此,我们着手鉴定具有神经保护作用并能减轻tau蛋白病变的类NAP肽。类NAP肽是通过公开可用的搜索引擎推导得出的,该搜索引擎在微管亚基微管蛋白和微管相关蛋白tau中鉴定出序列同源性。NATLSIHQ(NAT)和STPTAIPQ源自微管蛋白,而TAPVPMPD(TAP)源自tau蛋白。所有肽均对阿尔茨海默病(AD)毒素淀粉样β 1-42肽具有神经保护作用,尽管NAT和TAP的效力比STPTAIPQ强得多。NAT还能保护星形胶质细胞,而STPTAIPQ仅在微摩尔浓度时才有活性。由于NAT和TAP在神经保护方面比STPTAIPQ有效得多,因此还测试了这些肽对tau样聚集的抑制作用(AD的第二种蛋白质标志性病变)。NAT和TAP均抑制tau样聚集,NAT在非常宽的浓度范围内都有活性。在约10个月龄时进行测试时,NAT在额颞叶痴呆转基因小鼠模型(Tau-Tg)中也具有体内保护作用。结果显示,Tau-Tg小鼠大脑皮层中NAP母体蛋白(活性依赖性神经保护蛋白)的水平显著降低,而通过NAT治疗可使其恢复到正常水平。这与对受损Tau-Tg小鼠脑体重比的保护作用相关。鉴于AD是主要的tau蛋白病且tau蛋白参与额颞叶痴呆,新型的可减轻tau蛋白病并提供神经保护作用的NAP衍生物具有基础和临床研究价值。