The effect of aquaporin-4 mis-localization on Aβ deposition in mice.
The effect of aquaporin-4 mis-localization on Aβ deposition in mice.
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水通道蛋白 4 错误定位对小鼠 Aβ 沉积的影响。
DOI：
10.1016/j.nbd.2023.106100
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发表时间：
2023
影响因子：
6.1
通讯作者：
Iliff,JeffreyJ
中科院分区：
文献类型：
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作者：
Pedersen,TaylorJ;Keil,SamanthaA;Han,Warren;Wang,MarieX;Iliff,JeffreyJ
β-淀粉样蛋白 (Aβ) 清除率的降低被认为有助于与阿尔茨海默病 (AD) 相关的病理学发展，其特征是 Aβ 斑块的沉积。先前的研究表明，Aβ 通过类淋巴系统被清除，类淋巴系统是一个全脑血管周围通路网络，支持脑内脑脊液和间质液之间的交换。这种交换依赖于位于星形胶质细胞末端的水通道水通道蛋白-4 (AQP4)。虽然之前的研究表明 AQP4 的丢失和错误定位都会减缓 Aβ 清除并促进 Aβ 斑块形成，但 AQP4 的丢失或错误定位对 Aβ 沉积的相对影响从未直接比较过。在这项研究中，我们评估了 5XFAD 小鼠系内 Aβ 斑块的沉积如何受到 Aqp4 基因缺失或 α-肌营养蛋白 (Snta1) 敲除小鼠中 AQP4 定位缺失的影响。我们观察到，与 5XFAD 同窝小鼠对照相比，AQP4 的缺失 (Aqp4KO) 和错误定位 (Snta1KO) 均显着增加了脑实质 Aβ 斑块和微血管 Aβ 沉积。此外，AQP4 的错误定位对 Aβ 斑块沉积的影响比整体 Aqp4 基因缺失的影响更明显，这可能表明血管周围 AQP4 的错误定位在 AD 发病机制中发挥着关键作用。
The reduced clearance of amyloid-β (Aβ) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow Aβ clearance and promote Aβ plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aβ deposition has never been directly compared. In this study, we evaluated how the deposition of Aβ plaques within the 5XFAD mouse line is impacted by eitherAqp4gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4KO) and mislocalization (Snta1KO) of AQP4 significantly increases the parenchymal Aβ plaque and microvascular Aβ deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aβ plaque deposition than did globalAqp4gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.