11, Number 2, Special Issue "Free Radicals and Cell Signaling in Alzheimer's Disease" (Guest Editors: Alexander Boldyrev and Peter Johnson), May 2007
Alexander A. Boldyrev, Peter Johnson
Preface: Free Radicals and Cell Signaling in Alzheimer’s Disease
Robert B. Petersen, Akihiko Nunomura, Hyoung-gon Lee, Gemma Casadesus, George Perry, Mark A. Smith, Xiongwei Zhu
Signal Transduction Cascades Associated with Oxidative Stress in Alzheimer Disease
Abstract: It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.
Rukhsana Sultana, Debra Boyd-Kimball, Jain Cai, William M. Pierce, Jon B. Klein, Michael Merchant, D. Allan Butterfield
Proteomics analysis of the Alzheimer’s disease hippocampal proteome
Abstract: Alzheimer’s disease (AD) is characterized by the presence of intracellular neurofibrillary tangles (NFT), extracellular senile plaques (SP), and synaptic loss. The hippocampus is a region that plays an important role in memory and cognitive function, and it is severely affected in AD. The levels of proteins in the hippocampus may provide a better understanding of the pathological changes known. In the present study we used two-dimensional gel electrophoresis and mass spectrometry techniques to determine changes in protein levels in AD and control hippocampus. We identified 18 proteins with altered protein levels that are involved in regulating different cellular functions. Protein levels were found to be significantly decreased for peptidyl prolyl cis/trans-isomerase (Pin 1) (0.6-fold compared to control, p<0.03), dihydropyrimidinase-like protein 2 (DRP-2) (0.74-fold compared to control, p<0.02), phosphoglycerate mutase 1 (PGM1) (0.7-fold compared to control, p<0.01), beta-tubulin (0.34-fold compared to control, p<0.01), and aldolase A (0.87-fold compared to control, p<0.0002), whereas the protein levels were found to be significantly increased for enolase (1.35-fold compared to control, p<0.05), ubiquitin carboxyl terminal hydrolase L-1 (UCH L1) (1.31-fold compared to control, p<0.02), triosephosphate isomerase (TPI) (1.38-fold compared to control, p<0.05), carbonic anhydrase II (CAH-II) (1.24-fold compared to control, p=0.05), heat shock protein 70 (1.14-fold compared to control, p<0.03), fructose bisphosphate aldolase (1.38-fold compared to control, p<0.05), ferritin heavy chain (1.23-fold compared to control, p=0.05), 2’,3’-cyclic nucleotide 3’ phosphodiestrase (CNPase) (1.12-fold compared to control, p<0.02), peroxiredoxin II (1.39-fold compared to control, p<0.05), and adenylate kinase I (1.19-fold compared to control, p<0.03). We found 2 proteins spots that were identified as glyceraldehyde 3-phosphate dehydrogenase (GAPDH). One of the spots showed a 1.28-fold increase in protein level compared to control (p<0.01), and the other spot showed a similar 1.26-fold increase in protein level compared to control (p<0.04). Thus, proteomics has provided knowledge of the levels of key proteins in AD brain. We discuss the functions regulated by these proteins with respect to AD pathology.
Hajime Mori, Masayuki Oikawa, Tsuyoshi Tamagami, Hirokazu Kumaki, Reiko Nakaune, Jun Amano, Yukinori Akinaga, Koji Fukui, Kouichi Abe, Shiro Urano
Oxidized Proteins in Astrocytes Generated in a Hyperbaric Atmosphere Induce Neuronal Apoptosis
Abstract: In the present study, we investigated the influence of the oxidative damage to astrocytes on neuronal cell survival using cultures of rat cerebral astrocytes and neurons. The exposure of astrocytes to hyperbaric oxygen induced a time-dependent apoptotic cell death, as observed by DNA ladder assessment. When astrocytes damaged by oxidative stress were cocultured with normal neurons from the cerebrum of a newborn rat, neuronal cell death was markedly induced, although normal astrocytes not subjected to hyperoxia cocultured with normal neurons showed no neuronal cell apoptosis. It was found that either the supernatant from the homogenate of astrocytes cultured in hyperbaric oxygen atmosphere or a protein mixture extracted from the supernatant induced neuronal cell death. The level of protein carbonyls, an index of protein oxidation analysis, in cultured astrocytes increased significantly with oxidative stress, and vitamin E inhibited the increase in the level of such oxidized proteins in astrocytes. Furthermore, a two-dimensional (2D) electrophoresis of a protein mixture extracted from the supernatant showed several changes in proteins. These results imply that reactive oxygen species (ROS) induced by oxidative stress attack astrocytes to induce oxidatively denatured proteins in the cells that act as a neurotoxic factor, and that vitamin E protects neurons by inhibiting astrocyte apoptosis caused by oxidative stress.
Jose Viña, Ana Lloret, Soraya L. Vallés, Consuelo Borrás, Mari-Carmen Badía, Federico V. Pallardó, Juan Sastre, Maria-Dolores Alonso
Mitochondrial oxidant signalling in Alzheimer’s disease
Absract: The role of free radicals in Alzheimer disease pathophysiology has been appreciated for a long time. Originally, radicals were considered as causative of oxidative damage. More recently their role as signalling molecules in this, as well as in other fields of free radical biology, has been underscored. Mitochondria are both generators and targets of radical damage in aging. In this paper we review evidence that radicals generated in mitochondria in the presence of Aβ are signals that trigger both the mitochondrial and the extra-mitochondrial pathways of apoptosis. There are gender specific differences in mitochondrial Aβ toxicity: mitochondria from young (but not from old) females appear to be protected. 17-β Estradiol or phytoestrogens like genistein prevent the formation of oxidants by mitochondria and protect against mitochondrial Aβ toxicity. Experiments reported here indicate that phytoestrogens might have a role in the prevention of Alzheimer’s disease.
The involvement of lipid radical cycles and the adenine nucleotide translocator in neurodegenerative diseases
Abstract: The major cause of neurodegenerative disorders, including mid- to late-life onset Alzheimer’s disease, is permanent oxidative stress in the brain. Polyunsaturated fatty acids (PUFA) and α-tocopherol (α-TOH) are the most oxygen-sensitive constituents of cells. The presence of α-TOH in biological membranes is required but not sufficient to protect them against lipid peroxidation. The data presented in this review consider the role of α-TOH and cytochrome b5 which permit operation of lipid-radical cycles and the participation of lipid-radical reactions in key processes occurring in the membrane. Analysis of role of these cycles in membrane bioenergetics led us to a model involving the adenine nucleotide translocator and ATP synthesis in brain mitochondria. This paper summarizes experimental evidence for oxidative and non-oxidative pathways of PUFA metabolism with respective intermediates, which could be relevant to elucidation of new mechanisms of neurodegenerative diseases. Lipid-radical reactions in membranes work as important component of normal cell metabolism. Discussion is focused on the consequences of ineffective electron transfer to peroxyl radicals (LOO•→LOO‾) and excessive oxidative pathway of PUFA metabolism (LOO•→LOOH) with two reactive secondary products: malondialdehyde and methylglyoxal. Our future aim is to develop a more detailed model supplemented by the formation of lipofuscin and amyloid structures.
Ivan Shcherbatykh, David O. Carpenter
The Role of Metals in the Etiology of Alzheimer’s Disease
Abstract: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, affecting millions of men and women worldwide. It is characterized by the accumulation of extracellular amyloid β (Aβ) plaques and neurofibrillary tangles inside neurons and dystrophic neurons. Several risk factors are associated with the early onset and progression of the disease. Although the initiating molecular events are not entirely known, in recent years it has become evident that environmental and/or nutritional factors may play a causal, disruptive, and/or protective role in the development of AD. While a direct causal role for aluminum or other transition metals (copper, zinc, iron) in AD has not yet been definitively demonstrated, epidemiological evidence suggests that elevated levels of these metals in the brain may be linked to the development or progression of AD. This review summarizes studies which implicate a role for several metals in contributing to or causing AD.
Nitric Oxide and Nitroxidative Stress in Alzheimer’s Disease
Abstract: Nitric oxide is a signaling molecule produced by neurons and endothelial cells in the brain. NO is synthesized from L-arginine and oxygen by nitric oxide synthase: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). The endothelial NO acts as a vasorelaxant in the vasculature and as a neurotransmitter when produced by neurons (under the pathological conditions of Alzheimer’s disease). NO can be scavenged in a rapid reaction with superoxide (O2‾) to generate peroxynitrite (ONOO‾), with a half-life of <1s. ONOO‾ is a potent oxidant and the primary component of nitroxidative stress. At high concentrations (>100 nM), ONOO‾ can undergo homolytic or heterolytic cleavage to produce NO2+, NO2, and OH•, highly reactive oxidative species and secondary components of nitroxidative stress. The high nitroxidative stress can initiate a cascade of redox reactions which can trigger apoptosis and evoke cytotoxic effects on neurons and endothelial cells. This article reviews the functions of NO and the potential role of NO/O2‾/ONOO‾ induced nitroxidative stress in neuronal and endothelial degeneration observed in Alzheimer’s disease.
Alexander A. Boldyrev, Peter Johnson
Homocysteine and its derivatives as possible modulators of neuronal and non-neuronal cell glutamate receptors in Alzheimer’s disease
Abstract: Homocysteine (HC) and its derivatives may be involved in the etiology of Alzheimer’s disease (AD), although the precise mechanisms by which these compounds could cause cellular pathology are still unclear. Because interactions of HC with glutamate receptors have been implicated in AD, receptor-mediated effects of HC and homocysteic acid (HCA) on neurons and lymphocytes have been analyzed. Activation of glutamate receptors by these compounds has been shown to increase intracellular calcium and free radical levels in both types of cells, which may serve as a signal for development of apoptosis. Activation of group III metabotropic glutamate receptors stimulates, whereas activation of group I and group II metabotropic glutamate receptors prevent, the excitotoxic action of HC and HCA. These effects may contribute to the neuronal pathology and immunosenescence that occur in AD. It is proposed that selective agonists of metabotropic glutamate receptors that counter the effects of HC and its derivatives may be used for correction of neuronal and immune cell metabolism in vivo under the conditions of hyperhomocysteinemia, which can occur in AD.
Alan R. Hipkiss
Could carnosine or related structures suppress Alzheimer’s disease?
Abstract: Reactive oxygen species, reactive nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to Alzheimer’s disease (AD). Carnosine (ß-alanyl-L-histidine) is a naturally-occurring, pluripotent, homeostatic agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Amyloid peptide aggregates in AD brain are enriched in zinc ions. Carnosine can chelate zinc ions. Protein oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloid-β peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppress protein glycation. Glycated protein accumulates in the cerebrospinal fluid (CSF) of AD patients. Homocarnosine levels in human CSF dramatically decline with age. CSF composition and turnover is controlled by the choroid plexus which possesses a specific transporter for carnosine and homocarnosine. Carnosine reacts with protein carbonyls and suppress the reactivity of glycated proteins. Carbonic anhydrase (CA) activity is diminished in AD patient brains. Administration of CA activators improves learning in animals. Carnosine is a CA activator. Protein cross-links (gamma-glutamyl-e-amino) are present in neurofibrillary tangles in AD brain. Gamma-Glutamyl-carnosine has been isolated from biological tissue. Carnosine stimulates vimentin expression in cultured human fibroblasts. The protease oxidised-protein-hydrolase is co-expressed with vimentin. Carnosine stimulates proteolysis in cultured myocytes and senescent cultured fibroblasts. These observations suggest that carnosine and related structures should be explored for therapeutic potential towards AD and other neurodegenerative disorders.
Hypothesis: lifespan is regulated by chronomere DNA of the hypothalamus
Abstract: As the basis for the lifelong clock and as a primary cause of aging, a process of shortening of hypothetical perichromosomal DNA structures termed chronomeres is proposed in the CNS. The lifelong clock is regulated by the shortening of chronomere DNA in postmitotic neurons of the hypothalamus. Shortening of these DNA sequences occurs in humans on a monthly basis through a lunasensory system and is controlled by release of growth hormone discharged from the anterior pituitary directly into the hypothalamus via local blood vessels. In adults, this process is under control of the pineal gland. It is further proposed that different forms of Alzheimer's disease (AD) are caused by somatic and inherited deletions of chronomeres followed by a further abnormally accelerated decrease in their activity, resulting in failures of neurotrophic and neuroendocrinal activities and in various cellular imbalances. In this model, AD is considered as a segmental progeria caused by shortening of anomalous chronomeres that are partially deleted in early development. It is proposed that a calorie-restricted diet retards chronomere shortening due to a local deficit of growth hormone in the surroundings of hypothalamic cells, thus slowing the lifelong clock and delaying aging. Calorie restriction increases lifespan by preserving mitochondrial and other organismal functions owing to the decreased chronomere shortening.