重组 FOXN1 蛋白的给药可减轻小鼠的阿尔茨海默病病理。
Administration of recombinant FOXN1 protein attenuates Alzheimer's pathology in mice.
机构信息
Department of Allied Health Sciences, University of Connecticut, Storrs, CT, USA.
Department of Allied Health Sciences, University of Connecticut, Storrs, CT, USA; University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, USA.
出版信息
Brain Behav Immun. 2023 Oct;113:341-352. doi: 10.1016/j.bbi.2023.07.027. Epub 2023 Aug 2.
BACKGROUND
Alzheimer's disease (AD) is the most common cause of dementia in older adults and characterized by progressive loss of memory and cognitive functions that are associated with amyloid-beta (Aβ) plaques and neurofibrillary tangles. Immune cells play an important role in the clearance of Aβ deposits and neurofibrillary tangles. T cells are the major component of the immune system. The thymus is the primary organ for T cell generation. T cell development in the thymus depends on thymic epithelial cells (TECs). However, TECs undergo both qualitative and quantitative loss over time. We have previously reported that a recombinant (r) protein containing FOXN1 and a protein transduction domain can increase the number of TECs and subsequently increases the number of T cells in mice. In this study we determined the ability of rFOXN1 to affect cognitive performance and AD pathology in mice.
METHODS
Aged 3xTg-AD and APP/PS1 AD mice were injected with rFOXN1 or control protein. Cognitive performance, AD pathology, the thymic microenvironment and immune cells were then analyzed.
RESULTS
Administration of rFOXN1 into AD mice improves cognitive performance and reduces Aβ plaque load and phosphorylated tau in the brain. This is related to rejuvenating the aged thymic microenvironment, which results in enhanced T cell generation in the thymus, leading to increased number of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the brain, and the macrophage phagocytosis of Aβ are enhanced in rFOXN1-treated AD mice.
CONCLUSIONS
Our results suggest that rFOXN1 protein has the potential to provide a novel approach to treat AD patients.
背景
阿尔茨海默病（AD）是老年人中最常见的痴呆症病因，其特征是记忆和认知功能逐渐丧失，这与淀粉样β（Aβ）斑块和神经原纤维缠结有关。免疫细胞在清除 Aβ 沉积和神经原纤维缠结方面发挥着重要作用。T 细胞是免疫系统的主要组成部分。胸腺是 T 细胞生成的主要器官。T 细胞在胸腺中的发育依赖于胸腺上皮细胞（TEC）。然而，随着时间的推移，TEC 会发生质量和数量的损失。我们之前的研究表明，一种含有 FOXN1 和蛋白转导结构域的重组（r）蛋白可以增加 TEC 的数量，随后增加小鼠 T 细胞的数量。在这项研究中，我们确定了 rFOXN1 影响 AD 小鼠认知表现和 AD 病理的能力。
方法
对 3xTg-AD 和 APP/PS1 AD 老年小鼠进行 rFOXN1 或对照蛋白注射。然后分析认知表现、AD 病理、胸腺微环境和免疫细胞。
结果
rFOXN1 给药可改善 AD 小鼠的认知表现，并减少大脑中的 Aβ 斑块负荷和磷酸化 tau。这与使衰老的胸腺微环境年轻化有关，导致胸腺中 T 细胞的生成增强，从而导致脾脏和脉络丛（CP）中 T 细胞数量增加，尤其是 IFNγ 产生的 T 细胞，CP 中免疫细胞迁移分子的表达增强，单核细胞衍生的巨噬细胞向大脑的迁移增加。此外，rFOXN1 治疗的 AD 小鼠血清和大脑中抗 Aβ 抗体的产生以及巨噬细胞对 Aβ 的吞噬作用增强。
结论
我们的结果表明，rFOXN1 蛋白具有为 AD 患者提供新治疗方法的潜力。
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