Differential effects of aging on hippocampal ultrastructure in male vs. female rats.

Age-related decline in physical and cognitive functions are facts of life that do not affect everyone to the same extent. We had reported earlier that such cognitive decline is both sex- and context-dependent. Moreover, age-associated ultrastructural changes were observed in the hippocampus of male rats. In this study, we sought to determine potential differences in ultrastructural changes between male and female rats at various stages of life. We performed quantitative electron microscopic evaluation of hippocampal CA1 region, an area intimately involved in cognitive behavior, in both male and female adolescent, adult and old Wistar rats. Specifically, we measured the number of docking synaptic vesicles in axo-dendritic synapses, the length of active zone as well as the total number of synaptic vesicles. Distinct age- and sex-dependent effects were observed in several parameters. Thus, adult female rats had the lowest synaptic active zone compared to both adolescent and old female rats. Moreover, the same parameter was significantly lower in adult and old female rats compared to their male counterparts. On the other hand, old male rats had significantly lower number of total synaptic vesicles compared to both adolescent and adult male rats as well as compared to their female counterparts. Taken together, it may be suggested that age- and sex-dependent ultrastructural changes in the hippocampus may underlie at least some of the differences in cognitive functions among these groups.

Biochemical and Ultrastructural Changes in Wheat Plants during Drought Stress.

Drought severely slows down plant growth, decreases crop yield, and affects various physiological processes in plants. We examined four local bread wheat cultivars with different drought tolerance (drought-tolerant Zirva 85 and Murov 2 and drought-sensitive Aran and Gyzyl bughda cultivars). Leaves from seedlings of drought-tolerant plants demonstrated higher activity of antioxidant enzymes and lower levels of malondialdehyde and hydrogen peroxide. The content of soluble proteins in drought-exposed increased, possibly due to the stress-induced activation of gene expression and protein synthesis. Drought-exposed Zirva 85 plants exhibited an elevated activity of nitrogen and carbon metabolism enzymes. Ultrastructural analysis by transmission electron microscopy showed drought-induced damage to mesophyll cells and chloroplast membranes, although it was manifested less in the drought-tolerant cultivars. Comparative analysis of the activity of metabolic and antioxidant enzymes, as well as observed ultrastructural changes in drought-exposed plants revealed that the response to drought of seedlings was more pronounced in drought-tolerant cultivars. These findings can be used in further studies of drought stress in wheat plants under natural conditions.

Ultrastructural characteristics of the accumulation of iron nanoparticles in the intestine of Cyprinus carpio (Linnaeus, 1758) under aquaculture.

During the development of nanotechnology, the production of many substances containing nanoparticles leads to the release of various nanoparticles into the environment, including the water ecosystem. The main goal of the current research was to study the ultrastructural characteristics of the entry and bioaccumulation of Fe3O4 nanoparticles in the small intestine of Cyprinus carpio (Linnaeus, 1758), as well as the pathomorphological changes in the fish organism. Two different doses (10 and 100 mg) of Fe3O4 nanoparticles were fed to fingerlings for 7 days and then intestinal samples were taken and studied. It was found that the extent of damages was boosted within the increment of nanoparticle concentration. The sequence and bioaccumulation of Fe3O4 nanoparticles in the small intestine of fish occurred as below: firstly, the nanoparticles passed into microvilli located in the apical part of enterocytes in the mucosa layer, from there into the cytoplasm of the epithelial cells, including cytoplasmatic organelles (nucleus, mitochondria, lysosomes, fat granules), and then into a lamina propria of the mucosa of the small intestine and passed into the endothelium of the blood vessels and to the erythrocytes of the vessels which located in the lumen. It was determined that although the nanoparticles were up to 30 nm in size, only particles with a maximum size of 20 nm could penetrate the intestinal wall. Thus, the release of Fe3O4 nanoparticles into the environment in high doses has a negative effect on the living ecosystem, including the body of fish living in the water.

Experimental postoperative ileus: is Th2 immune response involved?

Rationale: Postoperative ileus (POI) is a frequent complication arising after gastrointestinal surgery but pathogenesis of POI is still not fully understood. While Th1 immune cells are implicated in POI, the involvement of Th2 cells has not yet been clarified. Given the impact of reactive oxygen species (ROS) in the regulation of Th1 and Th2 balance, we hypothesized that not only Th1 but also Th2 immune response can be involved in the development of experimental POI. Methods: The intestinal transit test was performed using carbon gum arabic. Electron microscopy was employed to assess tissue morphology and the presence of immune cells. Cytokines, IgE and ROS were measured. Immune cells from Peyer's patches were analyzed by Flow Cytometry and toluidine blue staining was used for detection of mast cells. Transcriptional factors were analyzed by Western blot. Results: POI is associated with an increase in both Th2 cytokines and Th2 cells. We have further demonstrated that POI induces a Th2-dependent activation of memory and non-memory B cells. This was accompanied by an increase in a number of mast cells in the colon of POI mice as well by an increased IgE and histamine plasma levels. We found that POI-induced accumulation of ROS was associated with an increased expression of the transcriptional factors HMBGI, NF-κB, and p38. This increased expression seemed to be associated with a Th2 response. Conclusion: Th2 immune response can be involved in the activation of mast cells in POI, which was associated with ROS mediated activation of NF-κB and p38 MAPK signaling pathway.

Investigation of an anticancer activity of combination of interferon-alpha and gemcitabine on pancreatic cancer cells.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is still a clinical challenge due to its deteriorated prognosis. Therefore, new combination chemotherapeutic approaches are of research interest. In this work, we attempted to characterize the effects of gemcitabine and interferon-alpha as well as the combination of both on the metabolic, pro-apoptotic, and proliferative activity of MiaPaca and Panc-1 cells. We showed that the exposure of both drugs in combination increases effectively the metabolic activity of cells of MiaPaca and Panc-1 cell lines compared to the monotherapies. Based on the data from the analysis of apoptosis, the underlying molecular effect of metabolic and proliferative inhibition is an increase in the number of cells in the early apoptosis. These data can be of interest in the context of future preclinical research.

Propionic acid affects the synaptic architecture of rat hippocampus and prefrontal cortex.

It is well documented that propionic acid (PPA) produces behavioral, morphological, molecular and immune responses in rats that are characteristic of autism spectrum disorder in humans. However, whether PPA affects the ultrastructure and synaptic architecture of regions of autistic brain has not been adequately addressed. Earlier we show that single intraperitoneal (IP) injection of PPA (175 mg/kg) produces superficial changes in the spatial memory and learning of adolescent male Wistar rats. However, in neurons, synapses and glial cells of hippocampal CA1 area and medial prefrontal cortex transient (mainly) or enduring alterations were detected. In this study, we used electron microscopic morphometric analysis to test the effect of PPA on different structural parameters of axodendritic synapses of the hippocampus and prefrontal cortex. The animals were treated with a single IP injection of PPA (175 mg/kg). The length and width of synaptic active zone, the area of presynaptic and postsynaptic mitochondria, the distance between presynaptic mitochondria and the synapse active zone, the distance between postsynaptic mitochondria and postsynaptic density and the depth and opening diameter of neuronal porosome complex were evaluated. Our results show that synaptic mitochondria of the hippocampus and prefrontal cortex are the most vulnerable to PPA treatment: in both regions, the area of postsynaptic mitochondria were increased. In general, our results show that even small dose of PPA, which produces only superficial effects on spatial memory and learning is able to alter the synapse architecture in brain regions involved in cognition and autism pathogenesis. Therefore, the microbiome may be involved in the control of neurotransmission in these regions.

Ultrastructural investigation of iron oxide nanoparticles accumulation in the liver of common carp (Cyprinus carpio Linnaeus, 1758).

In recent years, the intensive production of nanoparticles with a wide application has led to their transfer to the environment, including the water ecosystem. The accumulation of nanoparticles in fish, causing various pathological changes in the host, raises certain concerns. In the current study, we investigated the penetration and bioaccumulation of Fe3O4 nanoparticles, in the liver of common carp (Cyprinus carpio Linnaeus, 1758). Common carp juveniles were exposed to Fe3O4 nanoparticles at concentrations of 10 and 100 mg. After 7 days, their livers were examined by light and transmission electron microscopes. Compared to normal fish's liver, after using a small concentration (10 mg) of nanoparticles, changes were observed in erythrocytes, hepatocytes, intracellular canaliculi, and bile ducts of the liver. At a high concentration (100 mg), the intensity of changes increased significantly. The liver's capsule was damaged, and a considerable number of hepatocytes were completely destroyed. Additionally, the walls of blood vessels and biliary ductule walls was notably disturbed. It was found that the intensity of pathologies occurring in the liver, increases proportionally with higher concentrations of nanoparticles. Confirmation via electron microscopic methods revealed that Fe3O4 nanoparticles, when administered with food to common carp, enter the fish's liver through erythrocytes localized in the lumen of blood vessels. From there, they traverse through the endothelium of vessels, proceed to hepatocytes, including cytoplasmic organelles, intracellular canaliculi, biliary ductules, and eventually reach the bile ducts. Fe3O4 nanoparticles in all structural elements of fish liver was up to 20 nm. Therefore, high concentrations of nanoparticles in the environment harms the bodies of aquatic organisms, including fish. The changes identified in the liver of common carp in the present study are valuable information in assessing possible risks to other components of the aquatic ecosystem and organisms.

Effect of sulphidation process on the structure, morphology and optical properties of GO/AgNWs composites.

In this study, composite materials composed of graphene oxide (GO) synthesized by a modified Hummers' method and silver nanowires (AgNWs) synthesized by a modified polyol method were prepared. The prepared composites were subjected to sulfidation under the influence of H2S gas. Structural changes in the samples were evaluated using X-ray diffraction (XRD). The binding nature of the composite was characterized using FT-IR spectroscopy. Optical properties and band gap values were investigated using ultraviolet-visible (UV-Vis) spectroscopy. The morphology of the composites was analyzed by transmission electron microscopy (TEM). A simple method using H2S gas was applied for the sulphidation process of the samples. The sulfidation process was successful under the influence of H2S gas, resulting in an increased distance between the GO layers and a decrease in the band gap value for the composite post-sulfidation. In addition, AgNWs were observed to decompose into Ag2S nanoparticles under the influence of H2S gas. It was determined that the value of the band gap of the sample changes because of sulphidation.

Synthesis and Characterization of Novel Adsorbents Based on Functionalization of Graphene Oxide with Schiff Base and Reduced Schiff Base for Pesticide Removal.

Graphene oxide (GO) nanosheets were functionalized with Schiff base and reduced Schiff base. Covalent and non-covalent functionalized GO nanostructures have been tested for the removal of pesticides with different chemical structures and properties (e.g., Epoxiconazole, Dimethomorph, Cyprodinil, Chlorothalonil, Acetochlor, Trifluralin) from aqueous solutions. The structure and morphology characteristics of the prepared structures were analyzed using techniques such as solid-state nuclear magnetic resonance (SSNMR), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results of the experiments showed that, although the non-covalent functionalization did not affect the adsorption properties of GO much, the covalent functionalization increased the adsorption capacity of GO against the mentioned pesticides.

Preparation of anisotropic AgNWs/PVA/Ag2S nanocomposites via a vapor-phase sulfidation process.

This study used a modified polyol technique to synthesize silver nanowires (AgNWs), which were subsequently mixed with polyvinyl alcohol (PVA) polymer and air-dried under ambient conditions. As a result, AgNWs/PVA nanocomposites with a concentration of 2% were prepared by a casting process. After that, the upper surface of the produced samples was treated with H2S gas, as a result of which asymmetric structures were formed depending on the gas concentration, exposure time and penetration into the layers. The structural, morphological, and optical properties of these asymmetric structures were analyzed. Changes in the sample structure were studied using X-ray diffraction (XRD), their optical properties were studied using ultraviolet-visible (UV-Vis), Raman spectroscopy, and their morphology using Transmission electron microscopy (TEM). A simple technique involving H2S gas was used for the sulfidation process of the samples, marking the first exposure of AgNW/PVA nanocomposites to such treatment. Examination of the structural and optical properties of the surfaces revealed clear differences in their physical properties after sulfidation. These obtained results were also supported by TEM images. Finally, the successful production of AgNWs/PVA/Ag2S anisotropic structure was achieved by this method.

Synthesis, nanostructuring and in silico studies of a new imine bond containing a macroheterocycle as a promising PBP-2a non-ß-lactam inhibitor.

This study is devoted to the synthesis of a 40-membered macroheterocycle with its further nanostructuring by magnetite nanoparticles. The mentioned macroheterocycle was synthesized by the [2+2] cyclocondensation of the oxygen-containing diamine with an aromatic dialdehyde in a non-catalytic medium and with no work-up procedure. The structure of the obtained macroheterocycle was studied by 1H and 13C nuclear magnetic resonance spectroscopy and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Furthermore, the nanosupramolecular complex of macroheterocycles with magnetite nanoparticles was obtained and investigated by Fourier-transform infrared and ultraviolet-visible spectroscopy methods. Shifts in the infrared spectra of the nanosupramolecular complex indicate the interaction through metal-aromatic ring non-covalent bonding. The shift is also observed for the C-O-C stretching band of ether bonds. The loading rate of macroheterocycles on magnetite nanoparticles was 18.6%. The morphology of the ensemble was studied by transmission electron microscopy, which confirmed the synthesis of nanospherical particles with a diameter range of 10-20 nm. Powder X-ray diffraction analysis showed patterns of cubic Fe3O4 nanoparticles with a crystallite size equal to 9.1 nm. The macroheterocycle and its nanosupramolecular complex were tested against Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. The results have shown that the created complex has shown 64 times better activity against Staphylococcus aureus in comparison with the individual macroheterocycle and 32 times better activity in comparison with the pristine antibiotic Ampicillin as a control. In addition, computational analysis of the macroheterocycle was performed at the B3LYP/6-31G level in water. Molecular docking analyses for the macroheterocycle revealed Penicillin-binding protein PBP2a (5M18) from the transpeptidase family as a target protein in Staphylococcus aureus.

Age-related behavioral and ultrastructural changes in the rat amygdala.

Although the relationships between brain structure and emotions may alter across the life span, this relationship is of particular importance during aging when significant alterations in emotions may be manifested. Understanding the structural-behavioral relationship could not only provide a neurobiological basis of these changes, but could also suggest potential intervention. Since anxiety is commonly observed in aging population, we undertook this study to determine the extent of this behavioral manifestations as well as the associated ultrastructural changes in the amygdala. Rats of various age groups, adolescent, adult, and aged were tested for anxiety-like behavior and the ultrastructure/presynaptic architecture of the central nucleus of amygdala (CNA) were evaluated using transmission electron microscopy (EM). Aged rats were consistently more anxious than the other groups as evidenced by their scores in the elevated plus maze. Morphometric EM analysis of axodendritic synapses revealed that the aged rats had a lower presynaptic area as well as number of synapses, but unexpectedly a higher number of presynaptic mitochondria in CNA. Since presynaptic mitochondria are known to provide the energy for neurotransmission, it may be concluded that compensatory mechanisms are still operational during aging, and hence, may be a target for therapeutic intervention at this stage of life span.

Behavioral and neuroanatomical effects on exposure to White noise in rats.

Noise pollution is a severe public health problem as continuous exposure to even moderate noise levels between 55-65 dB can lead to various pathologies, including neurological states. In the present study, we assessed the ultrastructural alterations in selective auditory pathways of the rat brain following high intensity white noise exposure. In addition, learning, anxiety-like behavior and locomotor activity were assessed. Adult male rats were exposed to 100 dB noise, one hour daily, for 10 consecutive days. The evaluations were performed on day 11. Exposure to noise did not affect learning or the components of locomotor activity. However, it induced anxiety-like behavior as evidenced by time spent in the closed arm of elevated-plus maze. Concomitantly, ultrastructural changes in medial geniculate body, considered an integral component of classical auditory pathway, as well as in the hippocampus and basolateral amygdala, considered important structures of non-classical auditory pathway were noted. Specifically, noise resulted in neuronal apoptosis, chromatolysis, cytoplasmic organelle destruction, and glial activation in medial geniculate body and hippocampus, as well as mild alterations in amygdala. These results provide further evidence of detrimental consequences following exposure to loud noise.

Biochemical properties and ultrastructure of mesophyll and bundle sheath thylakoids from maize (Zea mays) chloroplasts.

A characteristic feature of C4 plants is the differentiation of the photosynthetic leaf tissues into two distinct cell types: mesophyll (M) and bundle sheath (BS) cells. We have investigated several biochemical parameters, including pigment composition, polypeptide patterns, fluorescence at 77K, the activity of photosystems and ultrastructure of mesophyll and bundle sheath chloroplasts of maize (Zea mays L.) plants. It is shown that the BS chloroplasts have ~2-fold higher chlorophyll a/b ratio than M chloroplasts, 6.15 and 3.12 respectively. The PSI apoprotein (68 kDa) was more abundant in BS than in M thylakoids. Polypeptides belonging to PSII core antenna, are in similar amounts in both types of membranes, but the 45kDa band is more intensive in M thylakoids. Polypeptides in the region of 28-24 kDa of the light-harvesting complex of PSII (LHCII) are also present in both types of chloroplasts, though their amounts are reduced in BS thylakoids. The chlorophyll fluorescence emission spectra in M cells showed the presence of three bands at 686, 695 and 735 nm characteristics of LHCII, PSII core and PSI complexes, respectively. However, in the fluorescence spectrum of agranal plastids, there are almost traces of the band at 695 nm, which belongs to the PSII core complex. The research results revealed that the photochemical activity of PSII in BS chloroplasts is ~5 times less than in the chloroplasts of M cells. The highest PSI activity was found in maize BS chloroplasts.

Exposure of rainbow trout (Oncorhynchus mykiss) to magnetite (Fe3O4) nanoparticles in simplified food chain: Study on ultrastructural characterization.

The widespread exposure of metallic nanoparticles to the aquatic ecosystem and its adverse impact on human life is the colossal concern worldwide. In view of this, this context was investigated to analyze microscopically the bioaccumulation and localization of magnetite (Fe3O4) nanoparticles in the cellular organelles of rainbow trout (Oncorhynchus mykiss, Walbaum, 1792) in aquatic conditions. Initially, Fe3O4 nanoparticles were absorbed on to Elodea (Elodea canadensis) and fed to molluscs (Melanopsis praemorsa). Fish were fed with the same molluscs, and then the intestines and liver were examined using light and transmission electron microscopy. Results showed that nanoparticles were present in the cytoplasm and other organelles of cells (mitochondrion and lysosome) by absorbing through microvilli of the epithelial cells of the tunica mucosa in the intestine. Further, nanoparticles passed through the vessels of the lamina propria of the tunica mucosa and reached to the sinusoids of the liver via blood circulation. It was then accumulated from the endothelium of the sinusoid to the cytoplasm of liver hepatocytes and to mitochondria and lysosome. The accumulation of nanoparticles in the epithelial cells, cytoplasm, mitochondria, and lysosome revealed the degree of transparency of the pattern with slight hesitation. In summary, this investigation contributed towards the understanding of the physiological effects of Fe3O4 nanoparticles on O. mykiss, which ascertains essentiality for sustainable development of nanobiotechnology in the aquatic ecosystem.

Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats.

Brain function declines with age and is associated with diminishing mitochondrial integrity. The neuronal mitochondrial ultrastructural changes of young (4 months) and old (21 months) F344 rats supplemented with two mitochondrial metabolites, acetyl-L-carnitine (ALCAR, 0.2%[wt/vol] in the drinking water) and R-alpha-lipoic acid (LA, 0.1%[wt/wt] in the chow), were analysed using qualitative and quantitative electron microscopy techniques. Two independent morphologists blinded to sample identity examined and scored all electron micrographs. Mitochondria were examined in each micrograph, and each structure was scored according to the degree of injury. Controls displayed an age-associated significant decrease in the number of intact mitochondria (P = 0.026) as well as an increase in mitochondria with broken cristae (P < 0.001) in the hippocampus as demonstrated by electron microscopic observations. Neuronal mitochondrial damage was associated with damage in vessel wall cells, especially vascular endothelial cells. Dietary supplementation of young and aged animals increased the proliferation of intact mitochondria and reduced the density of mitochondria associated with vacuoles and lipofuscin. Feeding old rats ALCAR and LA significantly reduced the number of severely damaged mitochondria (P = 0.02) and increased the number of intact mitochondria (P < 0.001) in the hippocampus. These results suggest that feeding ALCAR with LA may ameliorate age-associated mitochondrial ultrastructural decay and are consistent with previous studies showing improved brain function.

Effect of propionic acid on the morphology of the amygdala in adolescent male rats and their behavior.

Autism spectrum disorder is a group of life-long developmental syndromes, characterized by stereotypic behavior, restricted, communication deficits, cognitive and social impairments. Autism spectrum disorder is heritable state, provided by the mutations of well-conserved genes; however, it has been increasingly accepted, that most of such states are the result of complex interaction between individual's genetic profile and the environment that he/she is exposed to. Gut microbiota plays one of the central roles in the etiology of autism. Propionic acid is one of the most abundant short-chain fatty acids, made by enteric bacteria. Propionic acid has many positive functions and acts as the main mediator between nutrition, gut microbiota and brain physiology. However, increased level of propionic acid is associated with various neurological pathologies, including autism. It is proposed that some types of autism might be partially related with alterations in propionic acid metabolism. The amygdala, the main component of social brain, via its large interconnections with fronto-limbic neural system, plays one of the key roles in social communications, emotional memory and emotional processing. Social behavior is a hot topic in autism research. As to anxiety, it is not the main characteristics of ASD, but represents one of the most common its co morbidities. Several theoretical reasons compatible with amygdala dysfunction have been suggested to account for socio-emotional disturbances in autism. In the present study, using adolescent male Wistar rats, the effect of acute administration of low dose of propionic acid on social behavior, anxiety-like behavior and the structure/ultrastructure of central nucleus of amygdale was described. In addition to qualitative analysis, on electron microscopic level the quantitative analysis of some parameters of synapses was performed. Behavior was assessed 2, 24 and 48 hours after treatment. The results revealed that even single and relatively low dose of propionic acid is sufficient to produce fast and relatively long lasting (48 h after treatment) decrease of social motivation, whereas asocial motivation and emotional sphere remain unaffected. Morphological analyses of propionic acid-treated brain revealed the reduced neuron number and the increase of the number of glial cells. Electron microscopically, in some neurons the signs of apoptosis and chromatolysis were detected. Glial alterations were more common. Particularly, the activation of astrocytes and microglia were often observed. Pericapillary glia was the most changed. Neuronal, glial and presynaptic mitochondria showed substantial structural diversities, mainly in terms of size and form. Total number of the area of presynaptic profile was significantly decreased. Some axons were moderately demyelinated. In general, the data indicate that even low dose of propionic acid produces in adolescent rodents immediate changes in social behavior, and structural/ultrastructural alterations in amygdala. Ultrastructural alterations may reflect moderate modifications in functional networks of social brain.

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer's disease.

The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC) and C57B6/SJL Tg (+), which overexpress human amyloid beta precursor protein (AbetaPP). In situ hybridization using probes for normal and 5 kb deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Abeta peptide processed from AbetaPP, 8-hydroxy-2'-guanosine (8OHG), and cytochrome c oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions and structural abnormalities were present in the vascular walls of the human AD samples and the AbetaPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.

The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease.

Alzheimer's disease (AD) and stroke are two leading causes of age-associated dementia. A rapidly growing body of evidence indicates that increased oxidative stress from reactive oxygen radicals is associated with the aging process and age-related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases. New evidence has also indicated that vascular lesions are a key factor in the development of AD. This idea is based on a positive correlation between AD and cardiovascular and cerebrovascular diseases such as arterio- and atherosclerosis and ischemia/reperfusion injury. In this review we consider recent evidence supporting the existence of an intimate relationship between oxidative stress and vascular lesions in the pathobiology of AD. We also consider the opportunities for therapeutic interventions based on the molecular pathways involved with these causal relationships.

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

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.