Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice
Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice
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DOI：
10.1016/j.expneurol.2010.05.010
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发表时间：
2010-08-01
影响因子：
5.3
通讯作者：
Rosenmann, Hanna
中科院分区：
文献类型：
--
作者：
Boimel, Moran;Grigoriadis, Nikolaos;Rosenmann, Hanna
作为一种异常折叠和聚集的蛋白质，在阿尔茨海默病和其他tau蛋白病中由神经元缠结（NFT）组成的tau蛋白似乎是免疫治疗的候选者。然而，我们最近在免疫小鼠中报道的全长tau蛋白的致脑炎性要求仔细地和选择性地靶向病理性tau并解决功效（抗NFT作用）和安全性（无脑炎）。我们使用NET相关磷酸化（phos）tau肽免疫NFT小鼠，使用旨在使CNS中的促炎环境易感的免疫方案作为检测生物危害的设置，我们在检测全长tau的神经毒性时使用的方法[使用完全弗氏佐剂（CFA）和百日咳毒素（PT）]。CNS中的NFT负荷减少约40%，并伴随着小胶质细胞负荷的增加。在CNS的血清和血管中检测到抗磷酸化tau抗体，而没有记录到致脑炎性（无临床神经功能缺损、对脑炎性细胞的不良影响和轴突损伤）。溶酶体蛋白酶、组织蛋白酶D和L的水平，在免疫小鼠中受到影响，表明溶酶体系统可能参与NFT的减少。即使疫苗中包含具有PT的CFA，但在用β-tau肽免疫的NET小鼠中稳健的抗NFT作用和缺乏致脑炎性表明了它们的抗NFT治疗潜力。(C)2010年爱思唯尔公司All rights reserved.
As an abnormally folded and aggregated protein, tau composed of neurofibrillary tangles (NFTs) in Alzheimer's disease and other tauopathies seems to be a candidate for immunotherapy. Yet, the encephalitogenicity of full-length tau protein, recently reported by us in immunized mice, demands to carefully and selectively target pathological tau and address both efficacy (anti-NFT effect) and safety (free of encephalitis). We immunized NFT mice with NET-related phosphorylated (phos) tau peptides, using an immunization protocol aimed to predispose a proinflammatory milieu in CNS as a set up to detect biohazard, an approach we used when the neurotoxicity of full-length tau was detected [use of complete Freund adjuvant (CFA) with pertussis toxin (PT)]. A decrease of about 40% in NFT burden in CNS was demonstrated and was accompanied with an increase in microglial burden. Anti-phos-tau antibodies were detected in serum and blood vessels in the CNS, while no encephalitogenicity (free of clinical neurological deficits, of adverse effects on brain inflammatory cells and of axonal damage) was recorded. The level of the lysosomal proteases, cathepsins D and L., was affected in the immunized mice suggesting the possible involvement of the lysosomal system in the decrease of NFTs. The robust anti-NFT effect and the lack of encephalitogenicity in NET mice immunized with phos-tau peptides, even though CFA with PT was included in vaccine, point to their anti-NFT therapeutic potential. (C) 2010 Elsevier Inc. All rights reserved.