Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

被引:122
作者
Aliev, G
Smith, MA
Obrenovich, ME
De la Torre, JC
Perry, G
机构
[1] Case Western Reserve Univ, Microscopy Res Ctr, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
Alzheimer disease; vascular hypoperfusion; mitochondria; free radicals; metabolism; oxidative stress; neurodegeneration; AMYLOID-PRECURSOR-PROTEIN; CHROMOSOME TRANSGENIC MICE; BLOOD-BRAIN-BARRIER; NEURODEGENERATIVE DISEASES; NITRIC-OXIDE; ATHEROSCLEROTIC LESIONS; VULNERABLE NEURONS; WATANABE RABBITS; CENTRAL TARGET; BETA DEPOSITS;
D O I
10.1007/BF03033159
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion, may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium-derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.
引用
收藏
页码:491 / 504
页数:14
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