Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function
Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function
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DOI：
10.1046/j.1471-4159.2003.01973.x
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Brittian, KR
中科院分区：
文献类型：
--
作者：
Gozal, D;Row, BW;Brittian, KR
阻塞性睡眠呼吸暂停 (OSA) 是一种常见的疾病，其特征是睡眠期间间歇性缺氧 (IH)，与多个大脑区域的神经退行性变化以及学习缺陷有关。我们假设，在睡眠期间暴露于 IH 的老龄大鼠特别容易受到影响。因此，年轻（3-4 个月）和老年（20-22 个月）Sprague-Dawley 大鼠暴露于室内空气或 IH 中 14 天。使用莫里斯水迷宫的标准地点训练版本来评估学习和记忆。与暴露于室内空气 (RA) 或 IH 的年轻大鼠相比，暴露于室内空气 (RA) 或 IH 的老年大鼠表现出明显的空间学习障碍；此外，与年轻大鼠相比，随着年龄的增长，RA 和 IH 之间的性能下降明显更大 (p < 0.01)，并且与 IH 诱导的环 AMP 反应元件结合 (CREB) 磷酸化下降的幅度一致。此外，暴露于lH的年轻和老年大鼠的蛋白酶体活性均发生降低，但后者的程度要高得多（p < 0.001）。裂解的 caspase 3 表达表明，神经元凋亡在暴露于 IH 的老年大鼠中尤其增加（与暴露于 IH 的年轻大鼠相比，p < 0.01）。总的来说，这些发现表明衰老的啮齿动物大脑对 IH 具有独特的脆弱性，这至少部分反映在 CREB 磷酸化更显着的降低以及泛素-蛋白酶体途径明显无法充分清除降解的蛋白质上。
Obstructive sleep apnea (OSA) is a frequent medical condition characterized by intermittent hypoxia (IH) during sleep, and is associated with neurodegenerative changes in several brain regions along with learning deficits. We hypothesized that aging rats exposed to IH during sleep would be particularly susceptible. Young (3-4 months) and aging (20-22 months) Sprague-Dawley rats were therefore exposed to either room air or IH for 14 days. Learning and memory was assessed with a standard place-training version of the Morris water maze. Aging rats exposed to room air (RA) or IH displayed significant spatial learning impairments compared with similarly exposed young rats; furthermore, the decrements in performance between RA and IH were markedly greater in aging compared with young rats (p < 0.01), and coincided with the magnitude of IH-induced decreases in cyclic AMP response element binding (CREB) phosphorylation. Furthermore, decreases in proteasomal activity occurred in both young and aging rats exposed to lH, but were substantially greater in the latter (p < 0.001). Neuronal apoptosis, as shown by cleaved caspase 3 expression, was particularly increased in aging rats exposed to IH (p < 0.01 versus young rats exposed to IH). Collectively, these findings indicate unique vulnerability of the aging rodent brain to IH, which is reflected at least in part, by the more prominent decreases in CREB phosphorylation and a marked inability of the ubiquitin-proteasomal pathway to adequately clear degraded proteins.