Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer's disease.
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Journal Article↗
Biomedical subjects
G Perry
Publications and source records attributed to G Perry.
[Is the lesion produced by oxidation a central part in the pathogenesis of Alzheimer's disease?].
The two most striking features of Alzheimer's disease are: a) the multitude of abnormalities affecting essentially every system, and b) the strict age dependence. Recent work suggests that both features are linked to increased oxidative stress that damages lipids, proteins and nucleic acids and results in redox-active metal accumulations, mitochondrial damage and formation of advanced glycation endproducts. Interestingly, beta-protein precursor, amyloid-beta, presenilins and apolipoprotein E have all been linked to reactive oxygen species production or with apoptosis, a process intimately associated with oxidative stress. In therapeutics, the commonality between a number of efficacious agents appears to be oxidative stress reduction. Therefore, we contend that oxidative stress is the element that links the multitude of changes in Alzheimer's disease and that a reduction of oxidative stress will have a dramatic effect on reducing the incidence or progression of Alzheimer's disease.
Alzheimer Disease↗
Morphological features of regeneration of rabbit aortic endothelium after cryoinduced vascular damage.
Regeneration of endothelium after damage is an important factor, which limits the development of atherogenesis. This study examines the topographical characteristics of regenerating endothelial cells (EC) in rabbit aorta after de-endothelialization by cryodestruction. The effects of cloricromene on these processes were also studied. Vessels were harvested from 6-month-old NZW rabbits, 1 and 3 days after cryodestruction. The vessels were evaluated using scanning electron microscopy (SEM). One day after cryodestruction, there were defects in the endothelial monolayer in the zone of injury in saline treated animals. Large numbers of platelets and monocytes were observed in association with endothelium in the damaged zone. Three days after de-endothelialization the size of the area of the damage had decreased. On the surface of the new endothelial layer and below this defect, the number of adhering monocytes was increased, and many microdefects between endothelium could be seen. Administration of cloricromene for 1 or 3 days after damage reduced the number of endothelium-adherent platelets and monocytes, and microdefects in endothelium. The feature of endothelial repair in rabbits is a relatively large involvement of monocytes and platelets, which are visible below regenerated endothelium. Administration of cloricromene essentially restored re-endothelialization and significantly decreased the number of adherent monocytes and microdefects in the new endothelium.
Animals↗
Neuronal apoptosis--ISN satellite symposium. 5-7 August 1999, Tübingen, Germany.
This satellite meeting of the International Society of Neurochemistry was attended by over 100 investigators and was organized by Jörg Schulz and Pierluigi Nicotera (Neurodegeneration Laboratory, Department of Neurology, Universitat Tubingen). The symposium brought together leaders from various aspects of the field of cell death with the goal of understanding how neurons die in degenerative conditions. Rapid growth in this area has led to greater biological, pathological and therapeutic understanding of diseases considered to be intractable.
Journal Article↗
Striation is the characteristic neuritic abnormality in Alzheimer disease.
In this study, we found that neuropil threads of Alzheimer disease, rather than being continuous filaments along cell processes, show multiple interruptions. They are segmental in nature and therefore appear as striations rather than continuous filaments along the length of the neurite. Neuritic striation is not an artifact of section thickness since the majority of abnormal filament accumulations are extremely short. The dominance of short striations demonstrates that argyrophilic grains, rather than being distinct structures, simply represent a short variant of striation and that longer striations are arbitrarily considered neuropil threads. Ultrastructural examination showed that the intervals between striations lack a cytoskeleton. We suggest that neuritic striations may interrupt the microtubule system functionally blocking fast neuritic transport as well as playing a role in loss of neuronal connectivity.
Aged↗
Homocysteine and folate in healthy east London Bangladeshis.
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Adult↗
Dimethylargininase, a nitric oxide regulatory protein, in Alzheimer disease.
In this study, we show that dimethylargininase, a zinc protein involved in the regulation of nitric oxide synthase, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in Alzheimer disease (AD) while none of this enzyme was found in neurons in age-matched control cases. Seen in the context of earlier studies showing widespread nitric oxide related damage in AD and the role of dimethylargininase to activate nitric oxide synthetase, through catalytic removal of its endogenous inhibitors, these findings indicate major alterations in nitric oxide regulation in AD. Further, that low levels of zinc specifically inhibit dimethylargininase may provide a link between the numerous studies showing specific abnormalities in zinc and oxidative stress. Finally, our results provide additional evidence that oxidative stress- and nitric oxide-mediated events play important roles in the pathogenesis of AD.
Aged↗
Apoptosis and Alzheimer's disease.
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Alzheimer Disease↗
CI-ATPase and Na+/K(+)-ATPase activities in Alzheimer's disease brains.
The enzyme activities and the protein levels of Cl(-)-ATPase and Na+/K(+)-ATPase were examined in Alzheimer's disease (AD) brains. Cl(-)-ATPase and Na+/K(+)-ATPase activities in AD brains (n = 13) were significantly lower than those in age-matched control brains (n = 12). In contrast, there was no significant difference in anion-insensitive Mg2(+)-ATPase activity between the two groups. Western blot analysis revealed that the protein levels of Cl(-)-ATPase, Na+/K(+)-ATPase and neuron specific Na+/K(+)-ATPase alpha3 isoform were also significantly reduced in AD brains, while the amount of protein disulfide isomerase, one of the house keeping membrane proteins, was not different between the two groups. The data first demonstrated that Cl(-)-ATPase and Na+/K(+)-ATPase are selectively impaired in AD brains, which may reduce the gradients of Na(+), K(+) and Cl(-) across the cell membranes to cause excitotoxic cellular response and the resulting neuronal death.
Adenosine Triphosphatases↗
Cerebrovascular muscle atrophy is a feature of Alzheimer's disease.
We examined vascular amyloid-beta deposition and other abnormalities in the posterior cerebral artery of consecutive cases of Alzheimer's disease (AD) compared to controls. Smooth muscle atrophy was a consistent feature in the cases of AD examined (p<0.01) and was surprisingly independent of adjacent amyloid-beta deposition. These findings suggest that vascular abnormalities are a consistent feature in AD and may be an important contributor to the pathogenesis and complications of AD.
Adult↗
Abnormal localization of iron regulatory protein in Alzheimer's disease.
A role for altered iron metabolism in the pathogenesis of Alzheimer's disease has been suggested by several reports associating the cardinal neuropathologic lesions with markers of free radical-induced damage and redox-active iron. We hypothesized that the abnormal distribution of iron in Alzheimer brain might result from alterations in iron regulatory proteins (IRP) such as IRP-1 and IRP-2, the main control elements of cellular iron homeostasis. Here, we report that while IRP-1 is present at similar levels in both Alzheimer and control brain tissue, IRP-2 shows striking differences and is associated with intraneuronal lesions, including neurofibrillary tangles, senile plaque neurites and neuropil threads. Since IRP-2 colocalizes with redox-active iron, our results suggest that alterations in IRP-2 might be directly linked to impaired iron homeostasis in Alzheimer's disease.
Aged↗
Advanced lipid peroxidation end-products in Alexander's disease.
Rosenthal fibers (RF), intra-astrocytic hyaline inclusions, accumulate in various pathological conditions and are the histological hallmark of Alexander's disease. While the major protein components of RF have been identified, the factors accounting for their pathogenesis, accumulation, and insolubility are largely unknown. In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. In all the cases of Alexander's disease examined, strong immunolabeling of RF by the antibodies to 4-hydroxy-2-nonenal pyrrole adducts were noted. By contrast, age-matched control cases showed no immunoreactivity. These results indicate that modification of protein by lipid peroxidation adducts may play an important role in the formation of RF as well as in the pathogenesis of Alexander's disease. Furthermore, taken together with our previous data indicating advanced Maillard reaction end products in RF, it seems that post-translational modification of RF, initiated by oxidative stress, is critical for both the accumulation and the insolubility of RF, and therefore, by inference, in the pathogenesis of Alexander's disease.
Adolescent↗
Early glycoxidation damage in brains from Down's syndrome.
In Down's syndrome, the presence of three copies of chromosome 21 is associated with premature aging and progressive mental retardation sharing the pathological features of Alzheimer disease. Early cortical dysgenesis and late neuronal degeneration are probably caused by an overproduction of amyloid beta-peptide, followed by an increased cellular oxidation. Interestingly, chromosome 21 codes for superoxide-dismutase and amyloid beta precursor resulting, in Down's syndrome, in an overflow of these gene products and metabolites. We studied Down's fetal brain cortex to evaluate the presence and amount of lipid and protein oxidation markers; moreover, we quantified two forms of glycation end products that are known to be involved in the process of cellular oxidation. All these parameters are significantly increased in Down's fetal brains in comparison to controls, providing the evidence that accelerated brain glycoxidation occurs very early in the life of Down's syndrome subjects.
Aldehydes↗
Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease.
Recently, apoptosis has been implicated in the selective neuronal loss of Alzheimer's disease (AD). Apoptosis is regulated by the B cell leukemia-2 gene product (Bcl-2) family (Bcl-2, Bcl-x, Bax, Bak and Bad) and the caspase family (ICH-1 and CPP32), with apoptosis being prevented by Bcl-2 and Bcl-x, and promoted by Bax, Bak, Bad, ICH-1 and CPP32. In the present study, we examined the levels of these proteins in the membranous and cytosolic fractions of temporal cortex in AD and control brain. In the membranous fraction, the levels of Bcl-2 alpha, Bcl-xL, Bcl-x beta, Bak and Bad were increased in AD. In the cytosolic fractions, the level of Bcl-x beta was increased, while Bcl-xL, Bax, Bak, and Bad and ICH-1L were unchanged. CPP32 was not detected in AD or control brain. These findings demonstrate a differential involvement of cell death-regulatory proteins in AD and suggest that Bak, Bad, Bcl-2 and Bcl-x are upregulated in AD brains.
Age Factors↗
Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease.
We have developed an in vitro model in which isolated senile plaque (SP) cores are presented to rat microglial cells in culture. Microglia rapidly phagocytosed, broke apart, and cleared SP cores. However, when cocultured with astrocytes, microglial phagocytosis was markedly suppressed, allowing the SPs to persist. Suppression of phagocytosis by astrocytes appears to be a general phenomena since microglia in the presence of astrocytes showed reduced capacity to phagocytose latex beads as well. The astrocyte effect on microglia is related in part to a diffusible factor(s) since astrocyte- but not fibroblast-conditioned media also reduced phagocytosis. These results suggest that while microglia have the capacity to phagocytose and remove SPs, astrocytes which lie in close association to microglia may help prevent the efficient clearance of SP material allowing them to persist in Alzheimer's disease.
Alzheimer Disease↗
Alzheimer's disease--synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts.
Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, there is increasing evidence that the previously so-called "secondary factors" such as a disturbed glucose metabolism, oxidative stress and formation of "advanced glycation endproducts" (AGEs) and their interaction in a vicious cycle are also important for the onset and progression of AD. AGEs are protein modifications that contribute to the formation of the histopathological and biochemical hallmarks of AD: amyloid plaques, neurofibrillary tangles and activated microglia. Oxidative modifications are formed by a complex cascade of dehydration, oxidation and cyclisation reactions, subsequent to a non-enzymatic reaction of sugars with amino groups of proteins. Accumulation of AGE-crosslinked proteins throughout life is a general phenomenon of ageing. However, AGEs are more than just markers of ageing since they can also exert adverse biologic effects on tissues and cells, including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress). Oxidative stress is involved in various divergent events leading to cell damage, including an increase in membrane rigidity, DNA strand breaks and an impairment in glucose uptake. In addition, other age-related metabolic changes such as depletion of antioxidants or decreased energy production by a disturbed glucose metabolism diminish the ability of the cell to cope with the effects of radical-induced membrane, protein and DNA damage. With our improving understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the elucidation of the etiologic causes, particularly the positive feedback loops involving radical damage and a reduced glucose metabolism, will help to develop novel "neuroprotective" treatment strategies able to interrupt this vicious cycle of oxidative stress and energy shortage in AD.
Aging↗
What are the facts and artifacts of the pathogenesis and etiology of Alzheimer disease?
Over the past decade, an increased clinical awareness, together with advances in biochemical, cellular, and molecular analyses, have catapulted the study of Alzheimer disease to the forefront of biomedical research. During this time, a great number of theories, regarding disease pathogenesis, have come and gone but several have persisted. Here, we critically evaluate these theories in an attempt to delineate the facts from the artifacts.
Aged↗
A suicide note from Alzheimer disease neurons?
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Alzheimer Disease↗