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1.
J Neural Transm Suppl ; (65): 63-71, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12946049

RESUMO

In Alzheimer's disease, neurons in affected regions re-enter the cell cycle, leave the G0 state and appear to be arrested at both the G1/S and G2/M phase with resulting cell death, predominantly by apoptosis. Further hallmarks of AD are crosslinked protein deposits (amyloid plaques and neurofibrillary tangles), which time-dependently become modified by "advanced glycation endproducts (AGEs)". Since AGEs activate both mitogenic and redox-sensitive pathways, they might be involved both in cell cycle re-entry and arrest.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ciclo Celular , Produtos Finais de Glicação Avançada/metabolismo , Animais , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Estresse Oxidativo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Transdução de Sinais
2.
J Neural Transm Suppl ; (62): 303-7, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12456073

RESUMO

Accumulation of Advanced Glycation Endproducts (AGEs) in the brain is a feature of ageing and degeneration, especially in Alzheimer's disease (AD). Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking (beta-amyloid and MAP-tau), glial activation, oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. Combined intervention using antioxidants, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy.


Assuntos
Doença de Alzheimer/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Degeneração Neural/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Idoso , Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Humanos , Degeneração Neural/tratamento farmacológico
3.
Brain Res ; 920(1-2): 32-40, 2001 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-11716809

RESUMO

Advanced glycation endproducts (AGEs), protein-bound oxidation products of sugars, have been shown to be involved in the pathophysiological processes of Alzheimer's disease (AD). AGEs induce the expression of various pro-inflammatory cytokines and the inducible nitric oxide synthase (iNOS) leading to a state of oxidative stress. AGE modification and resulting crosslinking of protein deposits such as amyloid plaques may contribute to the oxidative stress occurring in AD. The aim of this study was to immunohistochemically compare the localization of AGEs and beta-amyloid (Abeta) with iNOS in the temporal cortex (Area 22) of normal and AD brains. In aged normal individuals as well as early stage AD brains (i.e. no pathological findings in isocortical areas), a few astrocytes showed co-localization of AGE and iNOS in the upper neuronal layers, compared with no astrocytes detected in young controls. In late AD brains, there was a much denser accumulation of astrocytes co-localized with AGE and iNOS in the deeper and particularly upper neuronal layers. Also, numerous neurons with diffuse AGE but not iNOS reactivity and some AGE and iNOS-positive microglia were demonstrated, compared with only a few AGE-reactive neurons and no microglia in controls. Finally, astrocytes co-localized with AGE and iNOS as well as AGE and were found surrounding mature but not diffuse amyloid plaques in the AD brain. Our results show that AGE-positive astrocytes and microglia in the AD brain express iNOS and support the evidence of an AGE-induced oxidative stress occurring in the vicinity of the characteristic lesions of AD. Hence activation of microglia and astrocytes by AGEs with subsequent oxidative stress and cytokine release may be an important progression factor in AD.


Assuntos
Doença de Alzheimer/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Óxido Nítrico Sintase/metabolismo , Idoso , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Indução Enzimática/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Microglia/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo II , Placa Amiloide/enzimologia , Placa Amiloide/patologia , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Inclusão do Tecido
4.
Z Gerontol Geriatr ; 34(6): 457-60, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11828884

RESUMO

Non-enzymatic glycation of proteins with reducing sugars and subsequent transition metal-catalyzed oxidations leads to the formation of protein-bound "advanced glycation endproducts" (AGEs). They accumulate on long-lived proteins including on and in the vicinity of the beta-amyloid plaques in Alzheimer's disease (AD). Since the AGE modification of a protein increases with time, and such a "long-term incubation" might also occur in the AD brain, we investigated whether an increase in the cytotoxic effects of an AGE-modified model protein occurs over time. Bovine serum albumin (BSA) was modified by glucose for defined time periods, and the viability of SH-SY5Y neuroblastoma cells, incubated with the differentially AGE-modified BSA samples, was measured with the MTT assay. Cytotoxicity of the AGE-modified BSAs increased in correlation to the incubation time with glucose. Among the AGE-specific markers, browning (OD 400) correlated best with cytotoxicity, followed by AGE-specific fluorescence and the defined AGE, carboxymethyllysine. Since AGEs accumulate in AD over time, they may be one of the "age-related" factors contributing to neuronal cell death in Alzheimer's disease.


Assuntos
Senescência Celular/fisiologia , Produtos Finais de Glicação Avançada/fisiologia , Idoso , Doença de Alzheimer/fisiopatologia , Animais , Produtos Finais de Glicação Avançada/toxicidade , Humanos , Neuroblastoma , Neurônios/fisiologia , Soroalbumina Bovina/toxicidade , Células Tumorais Cultivadas/fisiologia
5.
Eur J Neurosci ; 14(12): 1961-7, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11860491

RESUMO

Advanced glycation endproducts (AGEs) accumulate on long-lived protein deposits including beta-amyloid plaques in Alzheimer's disease (AD). AGE-modified amyloid deposits contain oxidized and nitrated proteins as markers of a chronic neuroinflammatory condition and are surrounded by activated microglial and astroglial cells. We show in this study that AGEs increase nitric oxide production by induction of the inducible nitric oxide synthase (iNOS) on the mRNA and protein level in the murine microglial cell line N-11. Membrane permeable antioxidants including oestrogen derivatives (e.g. 17beta-oestradiol) thiol antioxidants (e.g. (R+)-alpha-lipoic acid) and Gingko biloba extract EGb 761, but not phosphodiesterase inhibitors such as propentophylline, prevent the up-regulation of AGE-induced iNOS expression and NO production. These results indicate that oxygen free radicals serve as second messengers in AGE-induced pro-inflammatory signal transduction pathways. As this pharmacological mechanism is not only relevant for Alzheimer's disease, but also for many chronic inflammatory conditions, such membrane-permeable antioxidants could be regarded not only as antioxidant, but also as potent therapeutic anti-inflammatory drugs.


Assuntos
Doença de Alzheimer/enzimologia , Antioxidantes/farmacologia , Encefalite/enzimologia , Produtos Finais de Glicação Avançada/metabolismo , Microglia/enzimologia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Antioxidantes/uso terapêutico , Células Cultivadas , Relação Dose-Resposta a Droga , Encefalite/tratamento farmacológico , Encefalite/fisiopatologia , Radicais Livres/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/genética , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide/efeitos dos fármacos , Placa Amiloide/metabolismo , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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