Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China.
Department of Rehabilitation Sciences, University of Kentucky Center For Excellence in Rural Health, Hazard, KY, USA.
Int J Neuropsychopharmacol. 2012 Feb;15(1):55-68. doi: 10.1017/S1461145711000022. Epub 2011 Feb 1.
Astrocyte dysfunction is implicated in pathogenesis of certain neurological disorders including Alzheimer's disease (AD). A growing body of evidence indicates that water channel aquaporin-4 (AQP4) is a potential molecular target for the regulation astrocyte function. Recently, we reported that AQP4 expression was increased in the hippocampus of an AD mouse model established by long-term ovarian hormone deprivation combined with D-galactose (D-gal) exposure. However, pathophysiological roles and mechanisms of AQP4 up-regulation remain unclear. To address this issue, age-matched female wild-type and AQP4 null mice underwent ovariectomy, followed by D-gal administration for 8 wk. AQP4 null mice showed more severe brain oxidative stress, spatial learning and memory deficits, and basal forebrain cholinergic impairment than the wild-type controls. Notably, AQP4 null hippocampus contained more prominent amyloid-β production and loss of synapse-related proteins. These results suggested that ovariectomy and D-gal injection induced oxidative damage results in compensatory increases of AQP4 expression, and deficiency of AQP4 exacerbates brain oxidative stress and memory deficits. Therefore, regulation of astrocyte function by AQP4 may attenuate oxidative damage, offering a promising therapeutic strategy for AD.
星形胶质细胞功能障碍与某些神经退行性疾病的发病机制有关，包括阿尔茨海默病（AD）。越来越多的证据表明，水通道蛋白 aquaporin-4（AQP4）是调节星形胶质细胞功能的潜在分子靶点。最近，我们报道了在长期卵巢激素剥夺联合 D-半乳糖（D-gal）暴露建立的 AD 小鼠模型的海马体中 AQP4 表达增加。然而，AQP4 上调的病理生理作用和机制仍不清楚。为了解决这个问题，年龄匹配的雌性野生型和 AQP4 敲除小鼠接受卵巢切除术，然后接受 D-gal 处理 8 周。与野生型对照相比，AQP4 敲除小鼠表现出更严重的脑氧化应激、空间学习和记忆缺陷以及基底前脑胆碱能损伤。值得注意的是，AQP4 敲除的海马体中含有更明显的淀粉样β产生和突触相关蛋白的丢失。这些结果表明，卵巢切除术和 D-gal 注射引起的氧化损伤导致 AQP4 表达的代偿性增加，而 AQP4 的缺乏加剧了脑氧化应激和记忆缺陷。因此，AQP4 对星形胶质细胞功能的调节可能减轻氧化损伤，为 AD 提供了一种有前景的治疗策略。
