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

Abstract

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.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…As biopsy studies show morphological alterations of endothelial cells, the question arises whether these changes could "detach" astrocytes from the basement membrane of the BBB endothelium, creating a favourable condition for the inhibition of A efflux transporters. This hypothesis appears to be supported by the observation that the above morphological alterations precede the formation of perivascular A deposits [113]. Consistent with [112], another recent post mortem study [114] reported an inverse correlation between the burden of A senile plaques and P-gp positive capillaries.…”

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

“…Chronic hypoperfusion of the CNS in animal models induces mitochondrial energy failure and oxidative stress leading to neuronal death (19). White matter is more susceptible to chronic hypoperfusion than gray matter, with an involvement of axonal and myelin components (6).…”

l-3-n-Butylphthalide Improves Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

“…Bilateral permanent occlusion of the common carotid arteries (BCCAO) in rats results in a significant reduction in cerebral blood flow; therefore, it is a useful model of chronic cerebral hypoperfusion (Tsuchiya et al, 1993). This animal model exhibits learning and memory impairments resembling those found in AD and VaD, accompanied by neuronal degeneration and microvascular abnormalities (Farkas et al, 2004).It has been widely accepted that chronic cerebral hypoperfusion induces oxidative stress damage and brain energy failure in neuronal tissues and cells, at least partially due to the generation of reactive oxygen species and reactive nitrogen species (Aliev et al, 2003;de la Torre and Aliev, 2005). Reactive oxygen species are directly toxic to neurons, and They initiate a free-radical-mediated chain reactions resulting in neuronal system damage.…”

“…It has been widely accepted that chronic cerebral hypoperfusion induces oxidative stress damage and brain energy failure in neuronal tissues and cells, at least partially due to the generation of reactive oxygen species and reactive nitrogen species (Aliev et al, 2003;de la Torre and Aliev, 2005). Reactive oxygen species are directly toxic to neurons, and They initiate a free-radical-mediated chain reactions resulting in neuronal system damage.…”