An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome
An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome
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DOI：
10.1371/journal.pone.0152471
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发表时间：
2016-03-29
期刊：
影响因子：
3.7
通讯作者：
Mobley, William C.
中科院分区：
文献类型：
--
作者：
Belichenko, Pavel V.;Madani, Rime;Mobley, William C.
在唐氏综合征（DS）或21号染色体三体中，淀粉样前体蛋白（APP）的β-淀粉样蛋白（A β）肽产物过量存在。有证据表明，APP基因剂量增加和A β在DS患者经历的认知困难中起着关键作用。特别是，A β与老年痴呆症的出现有关，与阿尔茨海默病（AD）的神经病理学标志物有关。目前，没有针对DS患者A β相关发病机制的治疗。在本文中，我们使用了含有嵌入脂质体中的A β 1-15肽以及佐剂单磷酰脂质A（MPLA）的疫苗。DS模型Ts 65 Dn小鼠在5月龄时用抗A β疫苗免疫，并在8月龄时检查认知测量。测定基底前脑胆碱能神经元的状态和脑内APP及其蛋白水解产物的水平。Ts 65 Dn小鼠的免疫导致稳健的抗A β IgG滴度，证明疫苗打破自身耐受性的能力。疫苗诱导的抗体与A β反应，而与APP或其C末端片段的结合检测不到。Ts 65 Dn小鼠的疫苗接种导致脑A β水平相对于溶剂处理的Ts 65 Dn小鼠适度但非显著降低，导致A β水平与二倍体（2N）小鼠相似。重要的是，接种疫苗的Ts 65 Dn小鼠在新物体识别和背景恐惧条件反射测试中显示出记忆缺陷的解决，以及胆碱能神经元萎缩的减少。未观察到治疗不良反应;疫苗未导致炎症、细胞浸润或出血。这些数据首次表明，抗A β免疫方法可在DS小鼠模型中靶向A β相关病理学。
In Down syndrome (DS) or trisomy of chromosome 21, the beta-amyloid (A beta) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and A beta as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, A beta is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD). At present, no treatment targets A beta-related pathogenesis in people with DS. Herein we used a vaccine containing the A beta 1-15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-A beta vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-A beta IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with A beta without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain A beta levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of A beta as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-A beta immunotherapeutic approach may act to target A beta-related pathology in a mouse model of DS.