Impact of Acute High Glucose on Mitochondrial Function in a Model of Endothelial Cells: Role of PDGF-C.

An increase in plasma high glucose promotes endothelial dysfunction mainly through increasing mitochondrial ROS production. High glucose ROS-induced has been implicated in the fragmentation of the mitochondrial network, mainly by an unbalance expression of mitochondrial fusion and fission proteins. Mitochondrial dynamics alterations affect cellular bioenergetics. Here, we assessed the effect of PDGF-C on mitochondrial dynamics and glycolytic and mitochondrial metabolism in a model of endothelial dysfunction induced by high glucose. High glucose induced a fragmented mitochondrial phenotype associated with the reduced expression of OPA1 protein, high DRP1pSer616 levels and reduced basal respiration, maximal respiration, spare respiratory capacity, non-mitochondrial oxygen consumption and ATP production, regarding normal glucose. In these conditions, PDGF-C significantly increased the expression of OPA1 fusion protein, diminished DRP1pSer616 levels and restored the mitochondrial network. On mitochondrial function, PDGF-C increased the non-mitochondrial oxygen consumption diminished by high glucose conditions. These results suggest that PDGF-C modulates the damage induced by HG on the mitochondrial network and morphology of human aortic endothelial cells; additionally, it compensates for the alteration in the energetic phenotype induced by HG.

Structural insights from GRP78-NF-κB binding interactions: a computational approach to understand a possible neuroprotective pathway in brain injuries.

GRP78 participates in multiple functions in the cell during normal and pathological conditions, controlling calcium homeostasis, protein folding and Unfolded Protein Response. GRP78 is located in the endoplasmic reticulum, but it can change its location under stress, hypoxic and apoptotic conditions. NF-κB represents the keystone of the inflammatory process and regulates the transcription of several genes related with apoptosis, differentiation, and cell growth. The possible relationship between GRP78-NF-κB could support and explain several mechanisms that may regulate a variety of cell functions, especially following brain injuries. Although several reports show interactions between NF-κB and Heat Shock Proteins family members, there is a lack of information on how GRP78 may be interacting with NF-κB, and possibly regulating its downstream activation. Therefore, we assessed the computational predictions of the GRP78 (Chain A) and NF-κB complex (IkB alpha and p65) protein-protein interactions. The interaction interface of the docking model showed that the amino acids ASN 47, GLU 215, GLY 403 of GRP78 and THR 54, ASN 182 and HIS 184 of NF-κB are key residues involved in the docking. The electrostatic field between GRP78-NF-κB interfaces and Molecular Dynamic simulations support the possible interaction between the proteins. In conclusion, this work shed some light in the possible GRP78-NF-κB complex indicating key residues in this crosstalk, which may be used as an input for better drug design strategy targeting NF-κB downstream signaling as a new therapeutic approach following brain injuries.

Novel interactions of GRP78: UPR and estrogen responses in the brain.

Glucose-regulated protein 78 (GRP78; 78 kDa) belongs to a group of highly conserved heat shock proteins (Hsp) with important functions at the cellular level. The emerging interest for GRP78 relies on its different functions, both in normal and pathological circumstances. GRP78 regulates intracellular calcium, protein shaping, endoplasmic reticulum (ER) stress and cell survival by an immediate response to insults, and that its expression may also be regulated by estrogens. Although these roles are well explored, the mechanisms by which GRP78 induces these changes are not completely understood. In this review, we highlight various aspects related to the GRP78 functioning in cellular protection and repair in response to ER stress and unfolded protein response by the regulation of intracellular Ca(2+) and other mechanisms. In this respect, the novel interactions between GRP78 and estrogens, such as estradiol and others, are analyzed in the context of the central nervous system (CNS). We also discuss the importance of GRP78 and estrogens in brain diseases including ischemia, Alzheimer's and Huntington's disorders. Finally, the main protective mechanisms of GRP78 and estrogens during ER dysfunction in the brain are described, and the prospective roles of GRP78 in therapeutic processes.

Cellular and molecular mechanisms of antioxidants in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the degeneration and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been suggested that oxidative stress plays a role in the etiology and progression of PD. For instance, low levels of endogenous antioxidants, increased reactive species, augmented dopamine oxidation, and high iron levels have been found in brains from PD patients. In vitro and in vivo studies of Parkinson models evaluating natural and endogenous antioxidants such as polyphenols, coenzyme Q10, and vitamins A, C, and E have shown protective effects against oxidative-induced neuronal death. In this paper, we will review the mechanisms by which polyphenols and endogenous antioxidants can produce protection. Some of the mechanisms reviewed include: scavenging nitrogen and oxygen reactive species, regulation of signaling pathways associated with cell survival and inflammation, and inhibition of synphilin-1 and alpha-synuclein aggregation.

Effects of natural antioxidants in neurodegenerative disease.

Polyphenols are secondary metabolites with antioxidant properties and are abundant in the diet. Fruits, vegetables, herbs, and various drinks (tea, wine, and juices) are all sources of these molecules. Despite their abundance, investigations into the benefits of polyphenols in human health have only recently begun. Phenolic compounds have received increasing interest because of numerous epidemiological studies. These studies have suggested associations between the consumption of polyphenol-rich aliments and the prevention of chronic diseases, such as cancer, cardiovascular diseases, and neurodegenerative diseases. More specifically, in the last 10 years literature on the neuroprotective effects of a polyphenol-rich diet has grown considerably. It has been demonstrated, in various cell culture and animal models, that these metabolites are able to protect neuronal cells by attenuating oxidative stress and damage. However, it remains unclear as to how these compounds reach the brain, what concentrations are necessary, and what biologically active forms are needed to exert beneficial effects. Therefore, further research is needed to identify the molecular pathways and intracellular targets responsible for polyphenol's neuroprotective effects. The aim of this paper is to present various well-known dietary polyphenols and their mechanisms of neuroprotection with an emphasis on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Neuroprotective agents in brain injury: a partial failure?

Brain injury leads to inflammation, stress, and cell death. Neurons are more susceptible to injury than astrocytes, as they have limited antioxidant capacity, and rely heavily on their metabolic coupling with astrocytes to combat oxidative stress. Both normally and after brain injury, astrocytes support neurons by providing antioxidant protection, substrates for neuronal metabolism, and glutamate clearance. Although astrocytes are generally more resilient than neurons after injury, severe damage also results in astrocyte dysfunction, leading to increased neuronal death. This mini review provides a very insightful and brief overview on a few examples of promising neuroprotective compounds targeting astrocyte function, with specific attention on how these treatments alter astrocyte response or viability, and how this may be critical for neuronal survival following brain injury.

Role of platelet-derived growth factor c on endothelial dysfunction in cardiovascular diseases.

Loss of endothelial function is a common feature to all cardiovascular diseases (CVDs). One of the risk factors associated with the development of CVDs is the hyperglycaemia that occurs in patients with metabolic disorders such as Type 1 and Type 2 diabetes mellitus. Hyperglycaemia causes endothelial dysfunction through increased production of reactive oxygen species (ROS) from different cellular sources leading to oxidative stress. Vascular endothelial growth factor (VEGF) is essential in the stimulation and maintenance of endothelial functional aspects and, although it can mitigate the impact of ROS, VEGF-mediated signalling is partially inhibited in diabetes mellitus. The search for therapeutic strategies that preserve, protect and improve the functions of the endothelium is of great relevance in the investigation of CVDs associated with hyperglycaemia. Platelet-derived growth factor C (PDGF-C) is a peptide with angiogenic properties, independent of VEGF, that stimulates angiogenesis and revascularization of ischemic tissue. In a diabetic mouse model, PDGF-C stimulates mature endothelial cell migration, angiogenesis, endothelial progenitor cell mobilization, and increased neovascularization, and protects blood vessels in a retinal degeneration model activating anti-apoptosis and proliferation signalling pathways in endothelial cells. This review summarizes the information on the damage that high d-glucose causes on endothelial function and the beneficial effects that PDGF-CC could exert in this condition.

Oxidative Stress in ICU Patients: ROS as Mortality Long-Term Predictor.

Lipid peroxidation, protein oxidation, and mutations in mitochondrial DNA generate reactive oxygen species (ROS) that are involved in cell death and inflammatory response syndrome. ROS can also act as a signal in the intracellular pathways involved in normal cell growth and homeostasis, as well as in response to metabolic adaptations, autophagy, immunity, differentiation and cell aging, the latter of which is an important characteristic in acute and chronic pathologies. Thus, the measurement of ROS levels of critically ill patients, upon admission, enables a prediction not only of the severity of the inflammatory response, but also of its subsequent potential outcome. The aim of this study was to measure the levels of mitochondrial ROS (superoxide anion) in the peripheral blood lymphocytes within 24 h of admission and correlate them with survival at one year after ICU and hospital discharge. We designed an observational prospective study in 51 critical care patients, in which clinical variables and ROS production were identified and correlated with mortality at 12 months post-ICU hospitalization. Oxidative stress levels, measured as DHE fluorescence, show a positive correlation with increased long-term mortality. In ICU patients the major determinant of survival is oxidative stress, which determines inflammation and outlines the cellular response to inflammatory stimuli.

Mitochondrial Dysfunction in Intensive Care Unit Patients.

BACKGROUND: In patients admitted to the Intensive Care Unit (ICU), mortality is high due to multiple organ damage. Mitochondrial dysfunction and impaired oxygen consumption, as causative mechanisms, play a significant role in reducing the activity of immune cells in sepsis, resulting in the progression of the multiple organ dysfunction syndromes (MODS). The evaluation of mitochondrial function in critical care patients in the immune cells, especially in lymphocytes, could reveal the target point that determines mitochondrial failure. OBJECTIVE: To find the relationship between mitochondrial reactive oxygen species production (mROS), mitochondrial membrane potential (ΔΨm), and mitochondrial oxygen consumption (mVO2) in peripheral plasma lymphocytes collected from ICU patients. We also compared these three characteristic mitochondrial functions with C-reactive protein (CRP), serum lactate, and central venous saturation (SvO2) that would enable the prediction of the ultimate outcome. METHODS: Isolated lymphocytes from 54 critical care patients with SIRS by sepsis and non-sepsis etiologies were analyzed with flow cytometry by staining with dihydroethidium and JC-1, measuring mROS, ΔΨm, and mVO2. Clinical variables, such as serum lactate (mmol/L) and C-reactive protein (mg/L) from peripheral blood, were measured in the first 24 hours of admission. A confounding analysis was performed using logistic regression, and a p-value of <0.05 was considered statistically significant. RESULTS: It has been confirmed that there is a drastic increase in reactive oxygen species (ROS) and mVO2 in critically ill patients immediately after exposure to the insult pathogen-associated molecular pattern /damageassociated molecular pattern (PAMPS/DAMPS) and continued for the first 24 hours thereafter. The results showed no significant alterations in the mitochondrial membrane potential (ΔΨm) compared with the lymphocytes in controls. A significant correlation between CRP and SvO2 and a strong positive relationship between CRP, values above 3 mg/l, and white blood cells were observed. CONCLUSION: Lymphocytes from patients with SIRS displayed higher mitochondrial respiratory capacities and reactive oxygen species production compared with controls. Clinical markers of inflammation indirectly evaluate the mitochondrial function, most of which have been validated in a clinical setting.

Insights into cerebrovascular complications and Alzheimer disease through the selective loss of GRK2 regulation.

Alzheimer disease (AD) and stroke are two leading causes of age-associated dementia. Increasing evidence points to vascular damage as an early contributor to the development of AD and AD-like pathology. In this review, we discuss the role of G protein-coupled receptor kinase 2 (GRK2) as it relates to individuals affected by AD and how the cardiovasculature plays a role in AD pathogenesis. The possible involvement of GRKs in AD pathogenesis is an interesting notion, which may help bridge the gap in our understanding of the heartbrain connection in relation to neurovisceral damage and vascular complications in AD, since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium, and elsewhere. The aim of this review is to discuss our findings of overexpression of GRK2 in the context of the early pathogenesis of AD, because increased levels of GRK2 immunoreactivity were found in vulnerable neurons of AD patients as well as in a two-vessel occlusion (2-VO) mammalian model of ischaemia. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis, particularly in the context of cerebrovascular disease. We synthesize this newer information and attempt to put it into context with GRKs as regulators of diverse physiological cellular functions that could be appropriate targets for future pharmacological intervention.

Effect of 6-Shogaol on the Glucose Uptake and Survival of HT1080 Fibrosarcoma Cells.

Ginger is a plant that is native to southern China. In the last decade and research on the components of ginger has significantly increased; of these components, 6-shogaol exhibits the greatest potential antitumor capacity. However, the molecular mechanism through which 6-shogaol exerts its effects has not yet been elucidated. In this study, the effect of 6-shogaol on tumor cells that were derived from human fibrosarcoma (HT1080) was evaluated. Cell viability was determined by a (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay testing different concentrations of 6-shogaol (2.5-150 µM). Subsequently, the effect of 6-shogaol on reactive oxygen species (ROS) production, glucose uptake, and protein expression of the signaling pathway phosphatase and tensin homolog/ protein kinase B /mammalian target of rapamycin (PTEN/Akt/mTOR) was measured. 6-Shogaol reduced the viability of the tumor cells and caused an increase in ROS production, which was attenuated with the addition of N-acetylcysteine, and the recovery of cell viability was observed. The increase in ROS production in response to 6-shogaol was associated with cell death. Similarly, glucose uptake decreased with incremental concentrations of 6-shogaol, and an increase in the expression of mTOR-p and Akt-p proteins was observed; PTEN was active in all the treatments with 6-shogaol. Thus, the results suggest that cells activate uncontrolled signaling pathways, such as phosphoinositide 3-kinase (PI3K)/Akt/mTOR, among other alternative mechanisms of metabolic modulation and of survival in order to counteract the pro-oxidant effect of 6-shogaol and the decrease in glucose uptake. Interestingly, a differential response was observed when non-cancerous cells were treated with 6-shogaol.

Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs.

Astrocyte-mediated inflammation is associated with degenerative pathologies such as Alzheimer's and Parkinson's diseases and multiple sclerosis. The acute inflammation and morphological and metabolic changes that astrocytes develop after the insult are known as reactive astroglia or astrogliosis that is an important response to protect and repair the lesion. Astrocytes optimize their metabolism to produce lactate, glutamate, and ketone bodies in order to provide energy to the neurons that are deprived of nutrients upon insult. Firstly, we review the basis of inflammation and morphological changes of the different cell population implicated in reactive gliosis. Next, we discuss the more active metabolic pathways in healthy astrocytes and explain the metabolic response of astrocytes to the insult in different pathologies and which metabolic alterations generate complications in these diseases. We emphasize the role of peroxisome proliferator-activated receptors isotypes in the inflammatory and metabolic adaptation of astrogliosis developed in ischemia or neurodegenerative diseases. Based on results reported in astrocytes and other cells, we resume and hypothesize the effect of peroxisome proliferator-activated receptor (PPAR) activation with ligands on different metabolic pathways in order to supply energy to the neurons. The activation of selective PPAR isotype activity may serve as an input to better understand the role played by these receptors on the metabolic and inflammatory compensation of astrogliosis and might represent an opportunity to develop new therapeutic strategies against traumatic brain injuries and neurodegenerative diseases.

Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport.

Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.

Mechanisms of PDGFRalpha promiscuity and PDGFRbeta specificity in association with PDGFB.

Platelet-derived growth factor receptor alpha (PDGFRalpha) interacts with PDGFs A, B, C and AB, while PDGFRbeta binds to PDGFs B and D, thus suggesting that PDGFRalpha is more promiscuous than PDGFRbeta. The structural analysis of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes and a molecular explanation for the promiscuity of PDGFRalpha and the specificity of PDGFRbeta remain unclear. In the present study, we modeled the three extracellular domains of PDGFRalpha using a previous crystallographic structure of PDGFRbeta as a template. Additionally, we analyzed the interacting residues of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes using docking simulations. The validation of the resulting complexes was evaluated by molecular dynamics simulations. Structural analysis revealed that changes of non-aromatic amino acids in PDGFRalpha to aromatic amino acids in PDGFRbeta (I139F, P267F and N204Y) may be involved in the promiscuity of PDGFRalpha. Indeed, substitution of amino acids with few probabilities of rotamer changes in PDGFRbeta (M133A, N163E and N179S) and energy stability due to the formation of hydrogen bond in PDGFRbeta could explain the specificity of PDGFRbeta. These results may be used as an input for a better and more specific drug and peptide design targeting diseases related with the malfunction of PDGFs and PDGFRalpha such as cancer and atherosclerosis.

Nanoparticles as Alternative Strategies for Drug Delivery to the Alzheimer Brain: Electron Microscopy Ultrastructural Analysis.

One of the biggest problems and challenges for the development of new drugs and treatment strategies against Alzheimer Disease (AD) is the crossing of target drugs into the blood brain barrier. The use of nanoparticles in drug delivery therapy holds much promise in targeting remote tissues, and as a result many studies have attempted to study the ultrastructural localization of nanoparticles in various tissues. However, there are currently no in vivo studies demonstrating the ultrastructural distribution of nanoparticles in the brain. The aim of this study was to address how intraperitoneal injection of silver nanoparticles in the brain leads to leaking on the inter-endothelial contact and luminal plasma membrane, thus elucidating the possibility of penetrating into the most affected areas in the Alzheimer brain (vascular endothelium, perivascular, neuronal and glial cells). Our results show that the silver nanoparticles reached the brain and were found in hippocampal areas, indicating that they can be conjugated and used to deliver the drugs into the cell cytoplasm of the damaged brain cells. The present study can be useful for the development of novel drug delivering therapy and useful in understanding the delivery, distribution and effects of silver nanoparticles in AD brain tissue at cellular and subcellular level.

Computational Insights of the Interaction among Sea Anemones Neurotoxins and Kv1.3 Channel.

Sea anemone neurotoxins are peptides that interact with Na(+) and K(+) channels, resulting in specific alterations on their functions. Some of these neurotoxins (1ROO, 1BGK, 2K9E, 1BEI) are important for the treatment of about 80 autoimmune disorders because of their specificity for Kv1.3 channel. The aim of this study was to identify the common residues among these neurotoxins by computational methods, and establish whether there is a pattern useful for the future generation of a treatment for autoimmune diseases. Our results showed eight new key common residues between the studied neurotoxins interacting with a histidine ring and the selectivity filter of the receptor, thus showing a possible pattern of interaction. This knowledge may serve as an input for the design of more promising drugs for autoimmune treatments.

Platelets promote mitochondrial uncoupling and resistance to apoptosis in leukemia cells: a novel paradigm for the bone marrow microenvironment.

Here we report that leukemia cell lines and primary CD34+ leukemic blasts exposed to platelet rich plasma (PRP) or platelet lysates (PL) display increased resistance to apoptosis induced by mitochondria-targeted agents ABT-737 and CDDO-Me. Intriguingly, leukemia cells exposed to platelet components demonstrate a reduction in mitochondrial membrane potential (ΔΨM) and a transient increase in oxygen consumption, suggestive of mitochondrial uncoupling. Accompanying the ranolazine-sensitive increase in oxygen consumption, a reduction in triglyceride content was also observed in leukemia cells cultured with platelet components indicating that lipolysis and fatty acid oxidation may support the molecular reduction of oxygen in these cells. Mechanistically, platelet components antagonized Bax oligomerization in accordance with previous observations supporting an antiapoptotic role for fatty acid oxidation in leukemia cells. Lastly, substantiating the notion that mitochondrial uncoupling reduces oxidative stress, platelet components induced a marked decrease in basal and rotenone-induced superoxide levels in leukemia cells. Taken together, the decrease in ΔΨM, the transient increase in ranolazine-sensitive oxygen consumption, the reduction in triglyceride levels, and the reduced generation of superoxide, all accompanying the increased resistance to mitochondrial apoptosis, substantiate the hypothesis that platelets may contribute to the chemoprotective sanctuary of the bone marrow microenvironment via promotion of mitochondrial uncoupling.

Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): a Docking Study.

Three-dimensional models of the alpha- and beta-1 subunits of the calcium-activated potassium channel (BK) were predicted by threading modeling. A recursive approach comprising of sequence alignment and model building based on three templates was used to build these models, with the refinement of non-conserved regions carried out using threading techniques. The complex formed by the subunits was studied by means of docking techniques, using 3D models of the two subunits, and an approach based on rigid-body structures. Structural effects of the complex were analyzed with respect to hydrogen-bond interactions and binding-energy calculations. Potential interaction sites of the complex were determined by referencing a study of the difference accessible surface area (DASA) of the protein subunits in the complex.

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.

Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease.

Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense "hypoxic" mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.