Institute of Veterinary Physiology and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Cell Mol Life Sci. 2009 Nov;66(22):3555-63. doi: 10.1007/s00018-009-0141-0. Epub 2009 Sep 11.
The mammalian brain is extremely sensitive to alterations in cellular homeostasis as a result of environmental or physiological insults. In particular, hypoxic/ischemic challenges (i.e. reduced oxygen and/or glucose delivery) cause severe and detrimental alterations in brain function and can trigger neuronal cell death within minutes. Unfortunately, as we age, oxygen delivery to cells and tissues is impaired, thereby increasing the susceptibility of neurons to damage. Thus, hypoxic (neuronal) adaptation is significantly compromised during aging. Many neurological diseases, such as stroke, Alzheimer's disease (AD), Parkinson's disease and diabetes, are characterized by hypoxia, a state that is believed to only exacerbate disease progression. However, the contribution of hypoxia and hypoxia-mediated pathways to neurodegeneration remains unclear. This review discusses current evidence on the contribution of oxygen deprivation to AD, with an emphasis on hypoxia inducible transcription factor-1 (HIF-1)-mediated pathways and the association of AD with the cytoskeleton regulator cyclin-dependent kinase 5.
哺乳动物的大脑对外界环境或生理刺激导致的细胞内环境改变极为敏感。特别是，缺氧/缺血性挑战（即减少氧气和/或葡萄糖供应）会导致大脑功能严重且有害的改变，并在数分钟内引发神经元细胞死亡。不幸的是，随着年龄的增长，细胞和组织的氧气供应受到损害，从而增加了神经元受损的易感性。因此，在衰老过程中，缺氧（神经元）适应性显著受损。许多神经系统疾病，如中风、阿尔茨海默病（AD）、帕金森病和糖尿病，都以缺氧为特征，这种状态被认为只会加重疾病的进展。然而，缺氧及其介导的途径对神经退行性变的贡献仍不清楚。本文综述了目前关于氧气剥夺对 AD 的贡献的证据，重点讨论了缺氧诱导转录因子-1（HIF-1）介导的途径以及 AD 与细胞骨架调节因子周期蛋白依赖性激酶 5 的关联。
