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Hypoxic Preconditioning Ameliorates Amyloid-β Pathology and Longterm Cognitive Decline in AβPP/PS1 Transgenic Mice
Current Alzheimer Research ( IF 1.8 ) Pub Date : 2020-05-31 , DOI: 10.2174/1567205017666201007121730
Jian Zhang 1, 2 , Ji Zhang 3, 4, 5 , Xiao-Jia Li 3, 4 , Jun Xiao 3, 4 , Fang Ye 3, 4
Affiliation  

Background and Objective: Hypoxic Preconditioning (HPC) has been well established to trigger endogenous mechanisms of neuroprotection basing on models of hypoxic and ischemic diseases in the Central Nervous System (CNS). However, its effects against Alzheimer's Disease (AD) still lack substantial evidence and in-depth exploration. The present study aimed to investigate the impacts of HPC on AD-related memory decline and amyloid-β (Aβ) pathology in AβPP/PS1 transgenic mice.

Methods: Seven-week-old AβPP/PS1 transgenic mice were randomized into HPC and non-HPC groups. The HPC groups were treated with early and repetitive HPC for four weeks, while the non-HPC group was raised under normoxia condition. All the animals were then raised until the age of 28 weeks when Morris water maze tests were conducted to examine the animals’ spatial memory. Indicators for Aβ pathology (soluble Aβ levels and numbers of Aβ plaques) and the expression of relevant proteins were measured to explore potential mechanisms.

Results: The results showed that HPC ameliorated memory decline and Aβ pathology in AβPP/PS1 mice. The protein levels of Amyloid-β Precursor Protein (AβPP) and β-site APP Cleaving Enzyme 1 (BACE1) were reduced while that of Hypoxic inducible factor 1α (HIF-1α) was elevated in HPC groups.

Conclusion: HPC might be a promising strategy for AD intervention. Its potential protection might be realized via downregulating the expressions of AβPP and BACE1 and hence inhibiting Aβ pathology. Notably, HIF-1α might play a key role in mediating subsequent neuroadaptive changes following HPC.



中文翻译:

缺氧预处理可改善 AβPP/PS1 转基因小鼠的淀粉样蛋白-β 病理和长期认知衰退

背景和目的:基于中枢神经系统 (CNS) 缺氧和缺血性疾病模型,低氧预处理 (HPC) 已被很好地建立以触发神经保护的内源性机制。然而,其对阿尔茨海默病(AD)的作用仍缺乏实质性证据和深入探索。本研究旨在研究 HPC 对 AβPP/PS1 转基因小鼠 AD 相关记忆力减退和淀粉样蛋白-β (Aβ) 病理学的影响。

方法:将 7 周龄的 AβPP/PS1 转基因小鼠随机分为 HPC 组和非 HPC 组。HPC 组接受早期和重复 HPC 治疗 4 周,而非 HPC 组在常氧条件下饲养。然后将所有动物饲养至 28 周龄,此时进行莫里斯水迷宫测试以检查动物的空间记忆。测量 Aβ 病理学指标(可溶性 Aβ 水平和 Aβ 斑块数量)和相关蛋白质的表达,以探索潜在的机制。

结果:结果表明,HPC 改善了 AβPP/PS1 小鼠的记忆力下降和 Aβ 病理。在 HPC 组中,淀粉样蛋白 β 前体蛋白 (AβPP) 和 β 位点 APP 裂解酶 1 (BACE1) 的蛋白质水平降低,而缺氧诱导因子 1α (HIF-1α) 的蛋白质水平升高。

结论:HPC 可能是一种很有前景的 AD 干预策略。其潜在的保护作用可能是通过下调 AβPP 和 BACE1 的表达从而抑制 Aβ 病理学来实现的。值得注意的是,HIF-1α 可能在介导 HPC 后的后续神经适应变化中发挥关键作用。

更新日期:2020-05-31
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