Corujo-Ramirez Ana Mia, Dua Malvika, Yoo Ki Hyun, Oliveros Alfredo, Jang Mi-Hyeon
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA.
PREP, Neuroscience Track, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.
Int Neurourol J. 2020 Nov;24(Suppl 2):72-78. doi: 10.5213/inj.2040436.218. Epub 2020 Nov 23.
Aging is the most significant risk factor for neurodegenerative disorders that are typified by cognitive deficits. Our recent work utilizing BubR1 hypomorphic (BubR1H/H) mice, an accelerated aging model, has revealed that genetic inhibition of the endogenous Wnt pathway inhibitor secreted frizzled related protein 3 (sFRP3) plays a neuroprotective role. Neuroinflammation has been suggested as a pathological hallmark of age-related neurodegeneration mediating cognitive impairment. However, whether sFRP3 inhibition has a neuroprotective effect on neuroinflammatory gliosis in BubR1H/H mice is unknown.
To investigate neuroprotection from aging-related neuroinflammation by sFRP3 in vivo, we generated double Bub R1H/H;sfrp3 knockout mice and performed immunohistological analysis with cell type-specific markers for astrocytes (glial fibrillary acidic protein), and microglia (ionized calcium-binding adapter molecule 1). Given that the hippocampus is a brain structure critical for learning and memory, and is uniquely affected in aging-related neurodegeneration, we evaluated morphological changes on astrocytes and microglia via confocal imaging.
We demonstrate that BubR1H/H mice exhibit significantly increased levels of astrogliosis and an increased trend of microglial activation in the hilus and molecular layer of the young adult hippocampus, thus suggesting that BubR1 insufficiency accelerates glial reactivity. Importantly, our results further show that genetic inhibition of sFRP3 significantly recovers the astrogliosis and microglial activation observed in BubR1H/H mice, suggesting a critical neuroprotective role for sFRP3 in age-related neuroinflammation.
Our findings suggest that sFRP3 inhibition may represent a novel therapeutic strategy for neurodegeneration.
衰老是以认知缺陷为特征的神经退行性疾病的最重要风险因素。我们最近利用BubR1低表达（BubR1H/H）小鼠（一种加速衰老模型）开展的研究表明，对内源性Wnt通路抑制剂分泌型卷曲相关蛋白3（sFRP3）进行基因抑制具有神经保护作用。神经炎症被认为是介导认知障碍的与年龄相关的神经退行性变的病理标志。然而，sFRP3抑制对BubR1H/H小鼠的神经炎性胶质细胞增生是否具有神经保护作用尚不清楚。
为了在体内研究sFRP3对与衰老相关的神经炎症的神经保护作用，我们构建了BubR1H/H;sfrp3双敲除小鼠，并使用星形胶质细胞（胶质纤维酸性蛋白）和小胶质细胞（离子化钙结合衔接分子1）的细胞类型特异性标志物进行免疫组织学分析。鉴于海马体是对学习和记忆至关重要的脑结构，并且在与衰老相关的神经退行性变中受到独特影响，我们通过共聚焦成像评估星形胶质细胞和小胶质细胞的形态变化。
我们证明，BubR1H/H小鼠在年轻成年海马体的齿状回和分子层中星形胶质细胞增生水平显著升高，小胶质细胞活化有增加趋势，这表明BubR1功能不足会加速胶质细胞反应性。重要的是，我们的结果进一步表明，sFRP3的基因抑制可显著恢复在BubR1H/H小鼠中观察到的星形胶质细胞增生和小胶质细胞活化，这表明sFRP3在与年龄相关的神经炎症中起关键的神经保护作用。
我们的研究结果表明，抑制sFRP3可能代表一种治疗神经退行性变的新策略。
