ISSN:0304-324X    

DOI:10.1159/000213829

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0304-324X    

DOI:10.1159/000213830

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0304-324X    

DOI:10.1159/000213831

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Although a vast number of experimental investigations have focused on various aspects of Alzheimer’s disease (AD), the pathogenic mechanism of the disease has not been established. AD research is a dynamically changing field that has entertained a variety of hypotheses. Since most of the data pertaining to AD pathogenesis is obtained in postmortem tissue or in vitro experiments, researchers must play a game of ‘connect the dots’ to try to correlate the diverse aspects of the disease and generate hypotheses regarding the sequence of pathological events. This article reviews the current state of AD research, and presents three hypothetical models for disease progre

ISSN:0304-324X    

DOI:10.1159/000213832

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The models developed in our laboratory demonstrate that ageing initiates and progresses in the pineal gland. However, the ageing postponing effects of pineal grafting into older recipients cannot be explained by a simple maintenance and/or normalization of the night melatonin synthesis and release. We propose here that the pineal gland monitors and regulates, via its control of neuroendocrine function, the maintenance of ‘self-identity’ and the capacity of the immune system to recognize and react against any noxious, endogenous or exogenous agent. Senescence is characterized by the extinction of this central pineal function. The progressive decline of the self-recognition capacity distinguishes the typical diseases of ageing expressed as emergence of peripheral desynchronization and autoimmune, anaplastic, neoplastic and degenerative processes. Our approaches aim at a prevention and/or restoration of central pineal functi

ISSN:0304-324X    

DOI:10.1159/000213833

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

A growing amount of data using light and electron microscopy, immunocytochemistry, uptake of brain markers and metabolic studies suggest that the pathogenesis of Alzheimer’s disease may be due to impaired vascular delivery of nutrients to the brain. The bulk of this evidence indicates that cerebral capillary transport of glucose, oxygen and other vital nutrients is dysfunctional in Alzheimer brains due to abnormal nemo-dynamic flow patterns caused by structural deformities of the capillaries. Clinical disorders which can worsen cerebral blood flow, such as head injury, coronary artery disease, cerebrovas-cular ischemia or the presence of apolipoprotein E4 allele will increase the risk of Alzheimer’s dementia. By contrast, activities that increase cerebral blood flow during aging such as complex thinking patterns or the use of drugs to reduce vascular resistance, such as aspirin or NSAIDs, will reduce the risk or improve the status of Alzheimer’s disease. The production of neuritic plaques and neurofibrillary tangles may develop from the hypometabolic abnormalities caused by the impaired cerebromicrovasculature in Alzheimer brains. Such metabolic and cerebral blood flow changes are considerably less significant in age-matched control subjects. The major physiological, pathological and cognitive changes reported for Alzheimer’s disease appear to have a common denominator which is reflected by the physically distorted cerebromicrovessels and their inability to optimally deliver nutrients to the brain, a condition which ultimately disturbs neurono-glial homeo

ISSN:0304-324X    

DOI:10.1159/000213834

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Band 3, a ubiquitous membrane transport, regulatory, and structural protein, is represented in brain by at least 4 isoforms. Bands 3 in brain performs the same functions as it does in erythrocytes (RBC). It is susceptible to oxidative damage, which, ultimately, terminates its life and that of the cell. We examined the changes band 3 undergoes in Alzheimer’s disease (AD) because our previous studies suggest that band 3 is a pivotal protein in neurological disease. Because we hypothesize that AD is a total body disease, we examined peripheral blood cells as well as brain tissue to determine whether the same changes occur in both. Our results indicate that posttranslational changes occur in RBC band 3 that parallel changes in brain band 3. These include decreased 32P-phosphate labeling in vitro of band 3 polypeptides in brain and RBC, increased degradation of band 3, alterations in band 3 recognized by polyclonal and monoclonal antibodies, and decreased anion and glucose transport by blood cells. Serum autoantibodies to band 3 peptides 588-602 and 822-839 were increased in AD patients compared to controls. These band 3 residues lie in anion transport/binding regions. This is consistent with alteration of this region in AD since it is recognized as antigenically different by the patients’ immune system. Our data support an immunological component to AD. The finding that changes in RBC in AD reflect those in brain and can be recognized by antibodies should facilitate development of blood tests for diagnosis and monitoring, and early therapy. It is anticipated that identification of molecular sites of posttranslational modification of band 3 will enable us to design specific preventive and treatment strategies, and target drugs to crucial molecular si

ISSN:0304-324X    

DOI:10.1159/000213835

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

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 cytoskel-eton 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.

ISSN:0304-324X    

DOI:10.1159/000213836

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Immune factors such as cellular immunity, autoimmunity, and inflammation may play a pathogenic role in Alzheimer’s disease (AD), a neurodegenerative disorder. Based on immu-nologic dysregulation in many patients, a neuroautoimmunity (NAI) model is proposed which suggested a CD8+ cell-mediated mechanism (activated cytotoxic T lymphocytes); CD4+ suppressor/inducer (2H4+) cells may also be involved. Antibrain antibodies may contribute through a cell-specific autoimmune assault leading to neurodegeneration of the AD type. Thus, a cell-mediated autoimmune response against brain antigens may explain the immune subset of A

ISSN:0304-324X    

DOI:10.1159/000213837

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Hallmark lesions of Alzheimer’s disease (AD) are filled with reactive immunocompetent microglia, suggesting that immunological abberations may participate in the pathophysiology of this disorder. If immune-mediated processes are closely linked to neuronal breakdown it would be of importance to have a reliable means to detect these processes. Cerebro-spinal fluid microglial antibodies found mainly in AD patients are discussed as such potential sources. These antibodies recognize microglia in the developing rat brain, in neuronal cultures and on AD cortical biopsies. Treatment aimed at downregulating microglial is discussed and may have therapeutic significance for AD patients. Largely this review presents current opinions which support the concept that inflammation and similar immune mechanisms need to be considered as participating in AD patho-genesi

ISSN:0304-324X    

DOI:10.1159/000213838

出版商:S. Karger AG    

年代:1997

数据来源: Karger