Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease

Abstract

Mitochondrial dysfunction may be a principal underlying event in aging, including age-associated brain degeneration. Mitochondria provide energy for basic metabolic processes. Their decay with age impairs cellular metabolism and leads to a decline of cellular function. Alzheimer disease (AD) and cerebrovascular accidents (CVAs) are two leading causes of age-related dementia. Increasing evidence strongly supports the theory that oxidative stress, largely due to reactive oxygen species (ROS), induces mitochondrial damage, which arises from chronic hypoperfusion and is primarily responsible for the pathogenesis that underlies both disease processes. Mitochondrial membrane potential, respiratory control ratios and cellular oxygen consumption decline with age and correlate with increased oxidant production. The sustained hypoperfusion and oxidative stress in brain tissues can stimulate the expression of nitric oxide synthases (NOSs) and brain endothelium probably increase the accumulation of oxidative stress products, which therefore contributes to blood brain barrier (BBB) breakdown and brain parenchymal cell damage. Determining the mechanisms behind these imbalances may provide crucial information in the development of new, more effective therapies for stroke and AD patients in the near future.

Keywords: Alzheimer disease; antioxidants; hypometabolism; metabolism; mitochondria; neurodegeneration; oxidative stress.

Figure 1

Ultrastructural features of the brain biopsy from the age-matched control (A) and AD (B–D) patients are characterized by heterogeneous morphology: A. An intact microvessel shows the absence of any particular abnormalities in the ultrastructure of endothelial cells (EC) and perivascular cells. Mitochondria in EC are intact. Original magnification: X 13,900. B. Short-post-mortem (<2 h) brain tissue from AD patients shows microvessels with severe damage such as the presence of clusters of mitochondria–derived lysosomes (single arrow) and necrotic changes in the ultrastructure of the EC and perivascular cells. Original magnification: X 8,300. C. Capillary endothelium (from Figure 1–B), under higher magnification, shows the presence of a cluster of damaged mitochondria (single arrows) containing positive mitochondrial DNA (mtDNA) signals visualized by using in situ hybridization following indirect colloidal gold decoration (17 nm gold particles). Original magnification: X 46,000. D. AD brain biopsy. EC occupied only the small part of the vessel wall. Perivascular cells show the presence of large mitochondria derived vacuoles in their matrix. Adhesion of the activated platelets (PLT) to damaged endothelium. Original magnification: 8,300. Abbreviations used in figures: EC–Endothelial cells; ER–Erythrocyte; PLT–Platelets; VL–Vessel lumen (reprinted from [172] with permission).

Figure 2

Ultrastructural features of brain microvessels from AD brains characterized by heterogeneous morphology. mitochondria abnormality appeared A. Undamaged microvessel endothelium did not show any particular changes in their ultrastructure. Mitochondria also were intact (single arrows). However, the perivascular spaces contained large vacuolar structures (double arrow). Original magnification X 13,000. B. Vascular EC shows the presence of degenerative mitochondria (double arrow). Original magnification X 6,600. C. The presence of electron-dense hypoxic mitochondria (single arrows) coexists with the formation of mitochondria derived lysosomal structure in the cytoplasmic matrix of EC and perivascular cells (indicated by double arrow). Original magnification X 20,000. D. To be a permanent feature of vascular endothelium and perivascular cells where damage became visible (single and double arrows indicate hypoxic and completely damaged mitochondria, respectively). Original magnification X 20,000. Abbreviations used in figures: BM–basal membrane of endothelium; EC–endothelial cell; ER–erythrocyte; VL–vessel lumen (reprinted from [87] with permission).

Figure 3

The ultrastructural characteristics of neuronal mitochondria damage from AD brain biopsy. Neurons with different degree of ultrastructural lesions. In the neuronal cell body partially and completely damaged mitochondria (indicated by single arrows and double asterisk respectively in A and C). The lesioned mitochondria appeared to be a major substrate for the lipofuscin formation (double arrow). The electron dense hypoxic mitochondria are seen throughout the cell body and characterize the abnormal mitochondrial cristae. Original magnification: A and B X20,000 respectively. C and D X 16,000 respectively (reprinted from [172] with permission).

Figure 4

The ultrastructural characteristics of the neuronal mitochondria from AD brain biopsy. A. Neurons with different degrees of ultrastructural lesions. Partially and completely damaged mitochondria are mostly located in the neuronal cell body and coexist with lipofuscin formation. Original magnification X 5,000. B. Large numbers of electron-dense hypoxic mitochondria (indicated by single arrows) were present throughout the cell body and characterized the abnormal mitochondrial cristae. Original magnification: X 20,000. C. Partially (indicated by single arrow) and completely damaged (double arrow) mitochondria. Original magnification X 20,000. D. The neuronal cell body shows the presence of hypoxic mitochondria (indicated by single arrows) close to lipofuscin (double asterisk). Original magnification X 20,000. Abbreviations used in figure: N– neuronal nucleus (reprinted from [87] with permission).

Figure 5

The features of wild type (A) mitochondrial DNA (mtDNA) and 8-OHG (B–D) staining in the hippocampus of short post–mortem (<2 h) human AD brain. Post–mortem AD hippocampus shows that wild type mtDNA (17 nm gold) is associated with severely damaged mitochondria and mitochondria derived lysosomes (double asterisk). Any area containing lipofuscin did not show mtDNA containing positive gold particles. Original magnification X 26,000. B–D: Features of 8-OHG staining in post–mortem AD brain. 8-OHG containing positive signals (17 nm gold particles) was seen throughout neuronal cell body and within in the matrix of damaged mitochondria (single arrow). Non–damaged mitochondria (indicated by double arrows in Figure.5C) and lipofuscin (double asterisk in Figure. B and D) do not contain 8-OHG positive gold particles. Original magnification: X16,000, 26,000 and 33,000 respectively B, C and D (reprinted from [172] with permission).

Figure 6

The features of wild, 5kb deleted mitochondria DNA (mtDNA), and COX immunoreactivity in the hippocampus of a postmortem human AD case. A and B. Hippocampal neuron shows wild type mtDNA containing positive signals (17 nm colloidal gold) detection were seen in the completely damaged mitochondria or mitochondria derived lysosomes (single arrows). Areas containing lipofuscin (asterisk) did not show any mtDNA containing positive signals. Magnification X 26,000 and X 20,000, respectively A and B. C. 5kb deleted mtDNA containing gold particles (17 nm) were mostly located in mitochondria–derived lysosomes (single arrows). Original magnification X 33,000. D. Damaged, abnormal mitochondria shows COX positive containing gold particles in the matrix (single arrows, colloidal gold 17 nm). Original magnification X 26,000 (reprinted from [172] with permission).