Biomedical subjects

George Perry

Publications and source records attributed to George Perry.

At least 163 records · Page 9Linked to original sources

PubMed2002

Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins.

Amyloid deposits are primarily composed of the amyloid-beta protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding Abeta interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on Abeta may provide mechanistic insights regarding both amyloid formation and removal.

Amyloid beta-Peptides↗

PubMed2002

Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs?

Alzheimer disease (AD) is defined pathologically and diagnostically defined by amyloid-beta senile plaques and neurofibrillary tangles (NFT) composed of tau. From the time of their original description nearly a century ago, a major focus has been to understand the role that these lesions play in the pathogenesis of the disease. The majority favors the notion that these lesions cause the disease and therefore attempts at therapeutic intervention are focused on preventing lesions formation. However, this rationale may be misguided since new evidence from our laboratories and others suggest that the lesions not only occur as a by-product of the fundamental disease process but also that they may be protective.

Aging↗

PubMed2002

Role of the antioxidant ascorbate in hibernation and warming from hibernation.

Ground squirrels tolerate up to 90% reductions in cerebral blood flow during hibernation as well as rapid reperfusion upon periodic arousal from torpor without apparent neurological damage. Thus, hibernation is studied as a model of tolerance to cerebral ischemia and other types of brain injury. Metabolic suppression likely plays a primary adaptive role that allows hibernating species to tolerate dramatic fluctuations in blood flow. Several other aspects of hibernation physiology are also consistent with tolerance to ischemia and reperfusion suggesting that multiple neuroprotective adaptations may work in concert during hibernation. The purpose of the present work is to review evidence for enhanced antioxidant defense systems during hibernation, with a focus on ascorbate, and discuss potential roles of these antioxidants during hibernation. In concert with dramatic decreases in blood flow, nutrient and oxygen delivery, plasma concentrations of the antioxidant ascorbate [(Asc)p] increase 3-5-fold during hibernation. In contrast, during re-warming, [Asc]p declines at a relatively rapid rate that peaks at the time of maximal O(2) consumption. This peak in O(2) consumption also coincides with a brief rise in plasma urate concentration consistent with a surge in reactive oxygen species production. Overall, data suggest that elevated concentration of plasma ascorbate is poised for distribution to metabolically active tissues during the surge in oxidative metabolism that accompanies re-warming during hibernation. This pool of ascorbate, as well as increased expression of other antioxidant defense systems, may protect vulnerable tissues from oxidative stress during hibernation and re-warming from hibernation. Better understanding of the role of ascorbate in hibernation may guide use of ascorbate and other antioxidants in treatment of stroke, head trauma and neurodegenerative disease.

Animals↗

PubMed2002

Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response.

In this review, we consider comparative aspects of the biology and pathology of oxygen radicals in neurodegenerative disease and how these findings have influenced our concept of oxidative stress. The common definition of oxidative stress is a breach of antioxidant defenses by oxygen radicals leading to damage to critical molecules and disrupted physiology. Inherent in this definition is that oxidative stress is an unstable situation, for if there is net damage, viability of the system decreases with time, leading to disequilibria and death. While this circumstance defines acute conditions, such as stroke and head trauma which result in dysfunction and death, it does not fit physiological situations or chronic diseases closely aligned to normal physiology. Therefore, we propose that oxidative modifications in Alzheimer disease may actually serve as a homeostatic response to stress resulting in a shift of neuronal priority from normal function to basic survival. This phenomenon is comparable to normal physiological conditions of metabolic decrease, such as those seen in hibernation and estivation. Thus, Alzheimer disease could be seen as part of normal aging that includes additional pathology due to inadequate homeostatic response.

Alzheimer Disease↗

PubMed2002

The "Down's" side of mitochondria.

The mechanisms involved in the development of Alzheimer disease-type pathology in patients with Down's syndrome are unclear. However, a paper published in the February 28 issue of Neuron indicates that mitochondrial dysfunction is pivotally involved.

Alzheimer Disease↗

PubMed2002

The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors.

Exposure of neuronal cells to the Alzheimer's amyloid beta protein (Abeta) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against Abeta-mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against Abeta neurotoxicity. For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b). Abeta-mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin, no neuroprotection against Abeta toxicity was observed when we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structurally unrelated free-radical scavenger phenyl-N-t-butyl nitrone (PBN), were added to Abeta-containing culture media. This study demonstrates that the neuroprotective properties of melatonin against Abeta-mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent.

5-Methoxytryptamine↗

PubMed2002

Formation of aberrant phosphotau fibrillar polymers in neural cultured cells.

Here we show, for the first time, the in vitro formation of filamentous aggregates of phosphorylated tau protein in SH-SY5Y human neuroblastoma cells. The formation of such aberrant aggregates, similar to those occurring in vivo in Alzheimer's disease and other tauopathies, requires okadaic acid, a phosphatase inhibitor, to increase the level of phosphorylated tau, and hydroxynonenal, a product of oxidative stress that selectively adducts and modifies phosphorylated tau. Our findings suggest that both phosphorylation and oxidative modification are required for tau filament formation. Importantly, the in vitro formation of intracellular tau aggregates could be used as a model of tau polymerization and facilitate the development of novel therapeutic approaches.

Aldehydes↗

PubMed2002

Involvement of Maillard reactions in Alzheimer disease.

Maillard reactions have been explored by food chemists for many years. It is only recently that the advanced glycation end products (AGEs), the end products of the Maillard reaction, have been detected in a wide variety of diseases such as diabetes, atherosclerosis, cataractogenesis, Parkinson disease and Alzheimer disease (AD). In this review, we discuss the chemistry and biochemistry of AGE-related crosslinks such as pyrraline, pentosidine, carboxymethyllysine (CML), crosslines, imidazolidinones, and dilysine crosslinks (GOLD and MOLD), as well as their possible involvement in neurodegenerative conditions. Pentosidine and CML are found in elevated amounts in the major lesions of the AD brain. Glycation is also implicated in the formation of the paired helical filaments (PHF), a component of the neurofibrillary tangles (NFTs). Amyloid-beta peptide and proteins of the cerebrospinal fluid are also glycated in patients with AD. In order to ameliorate the effects of AGEs on AD pathology, various inhibitors of AGEs have been increasingly explored. It is hoped that understanding of the mechanism of the AGEs formation and their role in the neurodegeneration will result in novel therapeutics for neuroprotection.

Journal Article↗

PubMed2002

Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins.

Alzheimer's disease (AD) is characterized by the accumulation of fibrillar amyloid-beta (Abeta) peptides to form amyloid plaques. Understanding the balance of production and clearance of Abeta peptides is the key to elucidating amyloid plaque homeostasis. Microglia in the brain, associated with senile plaques, are likely to play a major role in maintaining this balance. Here, we show that heat-shock proteins (HSPs), such as HSP90, HSP70, and HSP32, induce the production of interleukin 6 and tumor necrosis factor alpha and increase the phagocytosis and clearance of Abeta peptides. This suggests that microglial interaction with Abeta peptides is highly regulated by HSPs. The mechanism of microglial activation by exogenous HSPs involves the nuclear factor kB and p38 mitogen-activated protein kinase pathways mediated by Toll-like receptor 4 activation. In AD brains, levels of HSP90 were increased in both the cytosolic and membranous fractions, and HSP90 was colocalized with amyloid plaques. These observations suggest that HSP-induced microglial activation may serve a neuroprotective role by facilitating Abeta clearance and cytokine production

Alzheimer Disease↗

PubMed2002

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.

We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-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 age-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, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.

Alzheimer Disease↗

PubMed2002

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.

Alzheimer Disease↗

PubMed2002

Alzheimer Disease and Oxidative Stress.

Research in Alzheimer disease has recently demonstrated compelling evidence on the importance of oxidative processes in its pathogenesis. Cellular changes show that oxidative stress is an event that precedes the appearance of the hallmark pathologies of the disease, neurofibrillary tangles, and senile plaques. While it is still unclear what the initial source of the oxidative stress is in Alzheimer disease, it is likely that the process is highly dependent on redox-active transition metals such as iron and copper. Further investigation into the role that oxidative stress mechanisms seem to play in the pathogenesis of Alzheimer disease may lead to novel clinical interventions.

Journal Article↗

PubMed2002

Iron: a pathological mediator of Alzheimer disease?

Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-beta peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-beta in these studies. In contrast, several recent studies have suggested that amyloid-beta may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-beta may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.

Alzheimer Disease↗

PubMed2002

Is Alzheimer's disease a mitochondrial disorder?

Cell bodies of neurons at risk of death in Alzheimer's disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes occur in all vulnerable neurons and are reduced in neurons that contain neurofibrillary pathology. In this review, the authors provide a summary of recent work that demonstrates key abnormalities that may play a part in initiating and promoting neuronal oxidative damage. Mitochondrial abnormalities are clearly involved as a source of reactive oxygen species that culminates in perikaryal oxidative damage. However, because mitochondria in AD do not exhibit striking evidence of oxidative damage, as would be expected if they produced free radicals directly, the authors suspected that abnormal mitochondria are responsible for supplying a key reactant, that once in the cytoplasm, releases radicals. Because abnormal mitochondria, H2O2 and redox-active iron are juxtaposed in the same AD neuron, it has all the markings of a "radical factory." The proximal causes of mitochondrial abnormalities likely involve reentry into the cell cycle, where organellokinesis and proliferation results in an increase of mitochondria and intermediately differentiated cells, with a consequent increase in turnover. Supporting this, the authors have considerable in vivo and in vitro evidence for mitotic disturbances in AD.

Alzheimer Disease↗

PubMed2002

The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications.

Abnormalities in the metabolism of the transition metals iron and copper have been demonstrated to play a crucial role in the pathogenesis of various neurodegenerative diseases. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed in this article in depth. While there is documented evidence for alterations in the homeostasis, redox-activity and localisation of transition metals, it is also important to realise that alterations in specific copper- and iron-containing metalloenzymes appear to play a crucial role in the neurodegenerative process. These changes provide the opportunity to identify pathways where modification of the disease process can occur, potentially offering opportunities for clinical intervention. As understanding of disease aetiology evolves, so do the tools with which diseases are treated. In this article, we examine not only the possible mechanism of disease but also how pharmaceuticals may intervene, from direct and indirect antioxidant therapy to strategies involving gene therapy.

Alzheimer Disease↗

PubMed2002

Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity.

OBJECTIVES: Stroke is a major cause of brain injury in Alaska. Since antioxidant levels are decreased in aged brain, the greater predisposition to neuronal death in stroke leading to subsequent neurodegeneration in aged individuals may be related to changes in oxidant balance. We studied the effect of the endogenous antioxidant melatonin on excitotoxic injury resulting from N-methyl-D-aspartate (NMDA)-induced damage by developing an organotypic mouse brain slice model. Our objective was to inhibit the effects of oxidative stress induced by NMDA in mouse brain slices, using melatonin. METHODS: An organotypic mouse brain slice culture was established at PO2 levels maintained between 80 - 100 mm Hg. NMDA, melatonin or both were added to the slices and antioxidant function was determined using the redox active iron assay as well as 8-OHG and HO-1 immunoassays. RESULTS: This slice system allows for better regulation of both NMDA and melatonin concentrations than can be achieved by in vivo studies. Supporting an antioxidant function, melatonin (100 microM) significantly decreased redox active iron, heme-oxygenase (HO-1) induction and 8-hydroxyguanosine (8-OHG) following NMDA (50-100 microM) insult. However, somewhat surprisingly, high concentrations of melatonin alone (1 mM), increased redox active iron levels and HO-1 induction. CONCLUSIONS: These results support the hypothesis that melatonin is a neuroprotective antioxidant. Our data also suggest that 1 mM melatonin may have detrimental effects.

Animals↗

PubMed2002

Labeling of cerebral amyloid beta deposits in vivo using intranasal basic fibroblast growth factor and serum amyloid P component in mice.

UNLABELLED: There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. METHODS: The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. RESULTS: Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in Tg mice without intranasal injection of the ligands. bFGF and SAP stained neurons around the rim of Abeta deposits and throughout the cortex in Tg mice. There was only weak staining of neurons in Tg mice without intranasal injection of bFGF and no staining of SAP in Tg mice without intranasal injection of SAP. No bFGF or SAP staining was evident in wild-type control mice. CONCLUSION: We report a novel noninvasive method for labeling Abeta plaques. This method may be modified for human studies using intranasal injection of radiolabeled ligands and imaging with SPECT or PET.

Administration, Intranasal↗

PubMed2001

High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal.

Protein adducts of the lipid peroxidation product trans-4-hydroxy-2-nonenal (HNE) are features of oxidative damage in neuronal cell bodies in Alzheimer's disease but are also seen in axons of normal as well as diseased individuals. In this study, focusing on the axons of the mouse sciatic nerve, we found that HNE adducts characterize axons of mice from birth to senility. Immunoblots of axonal proteins showed that HNE adducts are only detected in neurofilament heavy subunit (NFH) and, to a lesser extent, neurofilament medium subunit (NFM), both lysine-rich proteins, consistent with the adducts being limited to lysine residues. In vitro, HNE treatment of permeabilized sciatic nerve showed the same specificity, i.e. NFH and NFM are the only proteins that reacted with HNE, providing they are phosphorylated. Quantitative immunoblot analysis of two strains of mice ages 1-33 months showed that the levels of HNE adducts on NFH are consistent throughout life. Additionally, mice transgenic for human superoxide dismutase-1 with G85R mutation show no difference in HNE adduction to NFH compared with controls. Taken together, these studies indicate that HNE adduction to NFH is physiological, and its constancy from birth to senility as well as its dependence on phosphorylation argues that NFH and NFM modification may play a role in protecting the membrane-rich axon from toxic aldehydes resulting from oxidative damage.

Aldehydes↗