Neuronal anion exchange proteins in Alzheimer's disease pathology.

Anion exchange (AE) proteins are present in human neurons in the brain. Immunohistochemical data indicate that their apparent expression level increases with age, and especially with degeneration in Alzheimer's disease-affected brain areas. The increase in immunoreactivity is probably caused by changes in AE structure that lead to an increased accessibility of hitherto hidden epitopes. These epitopes correspond to regions in the membrane domain that are involved in generation of senescent cell-specific antigen from AE1 in aging erythrocytes. Elucidation of the molecular nature of these changes and the underlying mechanisms will lead to insight in the processes that govern aging- and degeneration-associated perturbation of membrane integrity. The functional consequences of changes in AE structure may range from acidosis and disturbance of cytoskeleton integrity to untimely or impaired recognition of neurons by microglia.

Erythrocyte aging in the demented elderly: a fluctuating process?

Measurement of erythrocyte aging parameters in patients with dementia indicates that an Alzheimer-related disturbance of the erythrocyte aging process may not be detectable until in the more advanced stages of the disease. Also, a strong fluctuation in the values of erythrocyte aging parameters, over a period of 15 months, was observed in patients with dementia, but not in age-matched control donors. This fluctuation was independent of the type and stage of dementia, and its cause remains to be elucidated. Such variability hampers the use of erythrocyte aging characteristics for the diagnosis of dementia. On the other hand, the aging-related erythrocyte IgG content may be a sensitive biomarker for disturbed systemic homeostasis in the elderly.

Erythrocyte aging characteristics in elderly individuals with beginning dementia.

An increase in erythrocyte-bound IgG and enhanced breakdown of the erythrocyte anion exchanger band 3, characteristics of normal erythrocyte aging are observed in old, healthy individuals when compared with young donors. These findings indicate that the rate of cellular aging increases with organismal aging. Results from previous studies on the same parameters have suggested that the erythrocyte aging process is disturbed in patients in advanced stages of Alzheimer type dementia, and in individuals with Down's syndrome who show no signs of dementia. In this study we find no changes in erythrocyte aging parameters in old individuals in beginning stages of dementia of various etiologies. We conclude that, in general, characteristics of disturbed erythrocyte aging cannot serve as presymptomatic markers of Alzheimer-type dementia.

Involvement of neuronal anion exchange proteins in cell death in Alzheimer's disease.

Anion exchange (AE) proteins are present in human neurons in the brain. Immunohistochemical data indicate that their apparent expression level increases with age, and especially with degeneration in Alzheimer's disease-affected brain areas. The increase in immunoreactivity is probably caused by changes in AE structure that lead to an increased accessibility of hitherto hidden epitopes. These epitopes correspond to regions in the membrane domain that are involved in generation of senescent cell-specific antigen from AE1 in aging erythrocytes. Elucidation of the molecular nature of these changes and the underlying mechanisms, will lead to insight in the processes that govern aging- and degeneration-associated perturbation of membrane integrity. AE-mediated chloride/bicarbonate exchange is a major component in the regulation of intracellular pH. The functional consequences of changes in AE structure may range from acidosis, disturbance of cytoskeleton integrity, and untimely or impaired recognition of cells by components of the immune system, such as microglia. A molecular and physiological description of these changes will establish AE proteins as valuable tools in elucidating the processes of normal aging, and the disturbances in aging-related diseases such as Alzheimer's disease.

Implications of aging- and degeneration-related changes in anion exchange proteins for the maintenance of neuronal homeostasis.

Fourier-transform infrared spectroscopy was applied to examine the nature and extent of changes in membrane composition and structure during the aging process of the human erythrocyte. Analysis of the Amide I region (1700-1600 cm-1) indicates an aging-related decrease in alpha-helical structure with a concomitant increase in beta-structure. These changes can be explained by structural changes in the erythrocyte anion exchanger (band 3 or AE1) molecules, that may be caused by fragmentation, but not by aggregation. Immunohistochemical analysis of human brain tissue shows an increase in neuronal AE protein expression with age and suggests an additional increase in Alzheimer's disease. Biochemical analyses indicate that the latter may be caused by conformational changes in the AE membrane domain that are similar to those observed in AE1 during erythrocyte aging. AE proteins provide a binding site for the cytoskeleton in neurons, and AE-catalyzed chloride/bicarbonate exchange plays a major role in maintenance of neuronal pH. Thus, changes in AE structure are likely to contribute to loss of neuron homeostasis during aging and in neurodegenerative diseases.

Erythrocyte anion transporter and antibrain immunoreactivity in chorea-acanthocytosis. A contribution to etiology, genetics, and diagnosis.

Novel structural and functional alterations in the erythrocyte anion transporter band 3 are described in one patient with definite, and in two patients with symptoms compatible with chorea-acanthocytosis, but without acanthocytes. Immunoblotting analysis shows increased fragmentation of band 3, and sulfate flux measurements indicate that anion transport activity is reduced in the erythrocytes of these patients. These changes are similar, but not identical to those observed during normal erythrocyte aging. In addition, distinct antibrain immunoreactivity was present in the plasma of these patients. A family study indicates that abnormal erythrocyte band 3 structure and function and antibrain immunoreactivity may be phenotypes of two independent, genetically determined factors, that are part of the heterogenic defect of chorea-acanthocytosis. The findings in the patients without acanthocytes indicate that the biochemical abnormalities may be related to a chorea-acanthocytosis-like, amyotrophic extrapyramidal movement disorder with axonal neuropathy. Measurement of erythrocyte sulfate transport and plasma antibrain immunoreactivity could be of use in establishing the diagnosis and further unravelling the genetic background of chorea-acanthocytosis and related syndromes.

Erythrocyte membrane changes of individuals with Down's syndrome in various stages of Alzheimer-type dementia.

An increase in erythrocyte-bound IgG, enhanced breakdown of band 3, and changes in erythrocyte anion transport characteristics are observed in individuals with Down's Syndrome. We interpret these data as indicative for a disturbance of normal erythrocyte aging. A comparison of three groups of individuals with Down's Syndrome in various stages of dementia of the Alzheimer type did not reveal a correlation between the erythrocyte membrane changes and age or stage of dementia. Considering previously obtained data on patients with senile dementia of the Alzheimer type (7), these results may signify that parameters of disturbed erythrocyte aging represent presymptomatic markers of Alzheimer-type dementia.

Blood viscosity during thrombolytic therapy with anistreplase in acute myocardial infarction.

It has been postulated that a reduction in blood viscosity due to degradation of plasma fibrinogen may be of benefit to patients with acute myocardial infarction (AMI), who are treated with thrombolytic agents. The aims of this study were to investigate the time course of rheologic parameters, to identify the principal factors determining blood viscosity, and to find possible correlations between viscosity and cardiac function during thrombolytic therapy with anistreplase. Therefore, the viscosity of whole blood and plasma and the hematocrit were measured before and at 10 time points after thrombolysis in 10 patients with AMI. In addition, plasma fibrinogen and fibrin(ogen) degradation products were determined. Immediately after the start of thrombolysis, the viscosity of blood (both at high and low shear rate) and plasma decreased significantly and continued to do so for 24 hours. The mean hematocrit also decreased markedly, and even after correction for these hematocrit changes, the reduction in blood viscosity remained significant: it decreased to 72% of pretreatment (measured at low shear rate), whereas the high-shear viscosity decreased to 95% of baseline. The viscosity of plasma significantly decreased from 1.39 +/- 0.13 mPa.s (mean +/- SD) before thrombolysis to 1.22 +/- 0.08 mPa.s after 2 hours. There was a rapid, nearly complete depletion in fibrinogen, followed by a striking rebound after the second day. The decrease in blood viscosity lasted for 2 days after anistreplase and was mainly accounted for by the reduction in hematocrit. The contribution of fibrinogen to blood viscosity appeared less prominent. Despite these rheologic changes, no improvement in cardiac output was noticed in the patients.

Proteins immunologically related to erythrocyte anion transporter band 3 are altered in brain areas affected by Alzheimer's disease.

Proteins immunologically related to the human erythrocyte anion transporter band 3 are present in neurons of the human neocortex and hippocampus. Immunocytochemical studies show increased band 3 immunoreactivity in neurons in the brains of patients with Alzheimer's disease. Immunoblot studies show the presence of band 3-like molecules in brain membrane fractions, and suggest changes in expression and/or processing of band 3-like molecules in Alzheimer's disease-affected regions. We postulate that alterations in membrane-bound, band 3-like molecules may reflect termination of neuronal lifespan in Alzheimer's disease.

Are thrombocyte membranes altered in Alzheimer's disease? A morphometric and biochemical study.

Morphometric analysis of thrombocytes from patients with Alzheimer's disease, from patients with multi-infarct dementia, and from young and age-matched healthy control donors, did not reveal any Alzheimer-related increase in internal membranes. Biochemical analysis showed a reduced cholesterol content of thrombocyte membrane preparations from Alzheimer patients relative to age-matched controls, but not relative to multi-infarct dementia patients. Overall distribution of protein kinase C activity (PKC) between cytosol and membrane, in resting as well as in activated thrombocytes from Alzheimer patients, was similar to that in the control groups. However, both Alzheimer and multi-infarct dementia patients had lower cytosolic levels of basal kinase and PKC activities than age-matched controls, while only Alzheimer patients had lower cytoskeletal PKC activity than controls.

Angiographically assessed coronary arterial patency and reocclusion in patients with acute myocardial infarction treated with anistreplase: results of the anistreplase reocclusion multicenter study (ARMS).

In this open multicenter study, 156 patients with acute myocardial infarction received 30 U of anistreplase intravenously over 5 minutes within 4 hours of the onset of chest pain. The patency of the infarct-related vessel was determined by coronary angiography 90 minutes after anistreplase treatment, and also 24 hours after treatment, in patients with a patent infarct-related vessel at 90 minutes, to assess the reocclusion rate. The investigators categorized the infarct-related vessel as patent or occluded, and 2 independent cardiologists graded the infarct-related vessel according to the Thrombolysis in Myocardial Infarction (TIMI) perfusion criteria. At the 90-minute assessment, 106 of 145 evaluable patients (73%) had patent infarct-related vessels, and 39 of 145 (27%) had occluded infarct-related vessels. Of the 139 independently assessed patients, 98 (71%) had TIMI grades 2 or 3 and 41 (29%) had TIMI grades 0 or 1. At the 24-hour assessment, 98 of 102 patients (96%) had a patent infarct-related vessel, and reocclusion had occurred in 4 of 102 patients (4%). Of the 94 independently assessed patients 90 (96%) had TIMI grades 2 or 3, and 4 (4%) had TIMI grades 0 or 1. The reliability of noninvasive parameters as indicators of achieved patency of the infarct-related vessel was estimated by means of correlation with patency assessed by coronary angiography. A significant correlation of 0.62 was found. The patency rate of 71 to 73% after use of anistreplase in patients with acute myocardial infarction corresponds with findings in earlier studies. The low reocclusion rate of 4% after use of anistreplase probably reflects the prolonged action of anistreplase.

Erythrocyte membrane characteristics indicate abnormal cellular aging in patients with Alzheimer's disease.

Erythrocytes from patients with Alzheimer's disease show signs of disturbance of the normal cellular aging process. Immunoblotting of erythrocyte membrane proteins from Alzheimer patients reveals increased breakdown of the anion transport protein band 3 in a majority of the cells, similar to what is observed in only a very small cell population during normal aging. These structural changes are accompanied by changes in anion transport characteristics, but the latter partially deviate from those observed during normal aging. The amount of erythrocyte-bound immunoglobulin G, the most direct and relevant parameter of erythrocyte aging, is significantly increased in Alzheimer patients relative to age-matched, healthy donors and to patients with multi-infarct dementia. These data indicate accelerated molecular breakdown of band 3 and premature appearance of senescent cell characteristics in erythrocytes from Alzheimer patients, and support the hypothesis that abnormal cellular aging may be involved in the etiology of the Alzheimer-specific pathology.

Alzheimer's disease and cellular aging: membrane-related events as clues to primary mechanisms.

A fast-increasing number of data indicate that Alzheimer's disease is a systemic disease, not restricted to the central nervous system. The nature of Alzheimer-related changes in peripheral cells confirms and emphasizes indications from biochemical and morphological studies in brain for the involvement of cellular membranes in this disease. Analysis of membrane changes in erythrocytes from Alzheimer patients suggests that the normal aging process of these cells is disturbed. These conclusions may form the basis for further studies leading to a better insight into the etiology of Alzheimer's disease and to the development of diagnostic tools.