Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care giv...
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Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease. Am J Med. 2000;109:577-585. (C) 2000 by Excerpta Medica, Inc.
Natural polyamines, spermidine and spermine, and their precursor putrescine, are of consider able importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effe...
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Natural polyamines, spermidine and spermine, and their precursor putrescine, are of consider able importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effects in the nervous system, including control of nucleic acid and protein synthesis, modulation of ionic channels and calcium-dependent transmitter release. The polyamine system is also known to be involved in various brain pathologic events (seizures, stroke, Alzheimer's disease and others). While cerebral polyamine concentrations and the activities of polyamine-metabolizing enzymes have been studied in great detail, much less is known about the cells that are responsible for cerebral polyamine synthesis and interconversion. With the present review the attempt is made to show how exact knowledge about the regional distribution and cellular localization of polyamines and the polyamine-synthesizing enzymatic machinery (and especially of L-ornithine decarboxylase) may help to better understand the functional interplay between polyamines and other endogenous agents (transmitters, receptors, growth factors neuroactive drugs etc.). Polyamines have been localized both in neurones and glial cells. However, the main cellular locus of the ODC is the neuron-both in the immature and adult central nervous system. Each period of normal brain development and ageing seems to have its own, characteristic temporo-spatial pattern of neuronal ODC expression. During strong functional activation (kindling, epileptic seizures, neural transplantation) astrocytes and other non-neuronal cells do also express ODC and other polyamine-metabolizing enzymes. Astroglial expression of ODC is accompanied by an increase in glial fibrillary acidic protein in these cells. This shift in the cellular mechanisms of polyamine metabolism is currently far from being understood. In human brain diseases (Alzheimer's disease, schizophrenia) certain neurones show an increased expression of ODC, the
The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model o...
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The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly upregulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical. illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins Induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function. (Am J Pathol 2003, 162:2041-2057)
Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Sin...
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Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similar to FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (Mis), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).
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