Alzheimer Disease: Obrenovich ME

Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. · Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA. · Mini Rev Med Chem. · Pubmed #18991755 No free full text.

Abstract: Alzheimer disease treatment has yet to yield a successful therapy that addresses the source of the damage found in brains. Of the varied proposed theories of AD etiology, reactive oxygen species (ROS) generation is cited as a common factor. Efforts to reduce the pathology associated with ROS via antioxidants therefore offer new hope to patients suffering from this devastative disease.

Webber KM, Casadesus G, Zhu X, Obrenovich ME, Atwood CS, Perry G, Bowen RL, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106. USA. · Curr Pharm Des. · Pubmed #16472159 No free full text.

Abstract: Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

Aliyev A, Seyidova D, Rzayev N, Obrenovich ME, Lamb BT, Chen SG, Smith MA, Perry G, de la Torre JC, Aliev G. · Microscopy Research Center, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurol Res. · Pubmed #15265272 No free full text.

Abstract: Nitric oxide (NO) is a short-life key bioregulatory active molecule in the cardiovascular, immune and nervous systems. NO is synthesized by converting L-arginine to L-citrulline by enzymes called NO synthase (NOS). The growing body of evidence strongly supports the theory that this molecule appears to be one of the key targets for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD) or other related dementia. The vascular content of NO activity appears especially to be a main contributor to this pathology before the over-expression of other NOS isoforms activity in a different brain cellular compartment. We speculate that pharmacological intervention using NO donors and/or NO suppressors will be able to delay or minimize the development of brain pathology and further progression of mental retardation.

Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G. · The Microscopy Research Center and Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA. · Neurotox Res. · Pubmed #14715433 No free full text.

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.

Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Brain Res Brain Res Rev. · Pubmed #14499458 No free full text.

Abstract: Although much maligned, the amyloid-beta (Abeta) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Abeta belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Abeta's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Abeta would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Abeta generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Abeta, and while evidence for direct Abeta neurotoxicity in vivo is scarce, we postulate that the product of Abeta's antioxidant activity, hydrogen peroxide (H(2)O(2)), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Abeta in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H(2)O(2) and/or Abeta generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Abeta, we suggest that the excessive removal of Abeta may prevent adequate chelation of metal ions and removal of O(2)(-z.ccirf;), leading to enhanced, rather than reduced, neuronal oxidative stress.

Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neurosci Res. · Pubmed #12391597 No free full text.

Abstract: Abnormalities in mitochondrial function relate to the spectrum of pathological changes seen in Alzheimer's disease. Here we review the causes and consequences of mitochondrial disturbances in Alzheimer's disease as well as how this information might impact on therapeutic approaches to this disease.

Obrenovich ME, Morales LA, Cobb CJ, Shenk JC, Méndez GM, Fischbach K, Smith MA, Qasimov EK, Perry G, Aliev G. · Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. · J Cell Mol Med. · Pubmed #19292735 No free full text.

Abstract: 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.

Aliev G, Gasimov E, Obrenovich ME, Fischbach K, Shenk JC, Smith MA, Perry G. · Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249-1664, USA. · Vasc Health Risk Manag. · Pubmed #18827923 links to  free full text

Abstract: 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.

Obrenovich ME, Smith MA, Siedlak SL, Chen SG, de la Torre JC, Perry G, Aliev G. · Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurotox Res. · Pubmed #17000469 No free full text.

Abstract: Heterotrimeric guanine nucleotide-binding (G) protein-coupled receptor kinases (GRKs) are cytosolic proteins that are known to contribute to the adaptation of the heptahelical G protein-coupled receptors (GPCRs) and to regulate downstream signals through these receptors. GPCRs mediate the action of messengers that are key modulators of cardiac and vascular cell function, such as growth and differentiation. GRKs are members of a multigene family, which are classified into three subfamilies and are found in cardiac, vascular and cerebral tissues. Increasing evidence strongly supports the hypothesis that vascular damage is an early contributor to the development of Alzheimer disease (AD) and/or other pathology that can mimic human AD. Based on this hypothesis, and since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium and elsewhere, we explored cellular and subcellular localization by immunoreactivity of G protein-coupled receptor kinase 2 (GRK2), also known as beta-adrenergic receptor kinase-1(betaARK1), in the early pathogenesis of AD and in ischemia reperfusion injury models of brain hypoperfusion. In the present study, we used the two-vessel carotid artery occlusion model, namely the 2-VO system that results in chronic brain hypoperfusion (CBH) and mimics mild cognitive impairment (MCI) and vascular changes in AD pathology. Our findings demonstrate the early overexpression of GRK2 member kinase in the cerebrovasculature, especially endothelial cells (EC) following CBH, as well as in select cells from human AD tissue. We found a significant increase in GRK2 immunoreactivity in the EC of AD patients and after CBH, which preceded any amyloid deposition. Since GRK2 activity is associated with certain compensatory changes in brain cellular compartments and in ischemic cardiac tissue, our findings suggest that chronic hypoperfusion initiates oxidative stress in these conditions and appears to be the main initiating injury stimulus for disruption of brain and cerebrovascular homeostasis and metabolism.

Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. · Microscopy Research Center, Department of Anatomy, Department of Pathology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA. · Neurol Res. · Pubmed #14503022 No free full text.

Abstract: Accumulating evidence strongly suggests that the AD brain is characterized by impairments in energy metabolism, and vascular hypoperfusion, whereby oxidative stress appears to be an especially important contributor to neuronal death and development of AD pathology. We hypothesized that mitochondria play a key role in the generation of reactive oxygen species, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartments in the AD brain. All of these changes have been found to accompany AD pathology. In this review we have outlined recent evidence from the literature and our own original studies concerning the role of mitochondrial abnormalities and vascular damage in the pathogenesis of AD and AD-like pathology in transgenic mice (as a model for human AD). We examined ultrastructural features of vascular lesions and mitochondria from vascular wall cells in human AD brain biopsies, in human short post-mortem brain tissues and in yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (A beta PP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA was performed along with immunocytochemistry using antibodies against amyloid beta precursor protein (A beta PP), 8-hydroxy-2'-guanosine (8OHG) and cytochrome C oxidase (COX) were studied at the electron microscopic levels. There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC and C57B6/SJL Tg(+) mice compared to aged-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC and C57B6/SJL Tg(+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kB) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg(+) mouse tissues and in aged-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8OHG and COX in the same cellular compartment. Our observations first time demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress induced damage.

Ogawa O, Zhu X, Lee HG, Raina A, Obrenovich ME, Bowser R, Ghanbari HA, Castellani RJ, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Acta Neuropathol. · Pubmed #12677454 No free full text.

Abstract: Despite their terminally differentiated status, vulnerable neurons in Alzheimer's disease (AD) display evidence of cell cycle activation, suggesting that mitotic dysfunction may be important in disease pathogenesis. To further delineate the role of mitotic processes in disease pathogenesis, we investigated phosphorylated histone H3, a key component involved in chromosome compaction during cell division. Consistent with an activation of the mitotic machinery, we found an increase in phosphorylated histone H3 in hippocampal neurons in AD. However, rather than within the nucleus as in actively dividing cells, activated phosphorylated histone H3 in AD is restricted to the neuronal cytoplasm despite activation of the mitotic machinery. Therefore, the aberrant cytoplasmic localization of phosphorylated histone H3 indicates a mitotic catastrophe that leads to neuronal dysfunction and neurodegeneration in AD.

Obrenovich ME, Joseph JA, Atwood CS, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Neurobiol Aging. · Pubmed #12470809 No free full text.

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