RESUMO
Neuropathological changes generated by human amyloid-beta peptide (Abeta) fibrils and Abeta-acetylcholinesterase (Abeta-AChE) complexes were compared in rat hippocampus in vivo. Results showed that Abeta-AChE complexes trigger a more dramatic response in situ than Abeta fibrils alone as characterized by the following features observed 8 weeks after treatment: 1). amyloid deposits were larger than those produced in the absence of AChE. In fact, AChE strongly stimulates rat Abeta aggregation in vitro as shown by turbidity measurements, Congo Red binding, as well as electron microscopy, suggesting that Abeta-AChE deposits observed in vivo probably recruited endogenous Abeta peptide; 2). the appearance of laminin expressing neurons surrounding Abeta-AChE deposits (such deposits are resistant to disaggregation by laminin in vitro); 3). an extensive astrocytosis revealed by both glial fibrillary acidic protein immunoreactivity and number counting of reactive hypertrophic astrocytes; and 4). a stronger neuronal cell loss in comparison with Abeta-injected animals. We conclude that the hippocampal injection of Abeta-AChE complexes results in the appearance of some features reminiscent of Alzheimer-like lesions in rat brain. Our studies are consistent with the notion that Abeta-AChE complexes are more toxic than Abeta fibrils and that AChE triggered some of the neurodegenerative changes observed in Alzheimer's disease brains.
Assuntos
Acetilcolinesterase/toxicidade , Precursor de Proteína beta-Amiloide/toxicidade , Astrócitos/patologia , Gliose/patologia , Hipocampo/patologia , Laminina/genética , Neurônios/patologia , Animais , Astrócitos/efeitos dos fármacos , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/análise , Gliose/induzido quimicamente , Hipocampo/efeitos dos fármacos , Humanos , Processamento de Imagem Assistida por Computador , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espectrometria de FluorescênciaRESUMO
Alzheimer's disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury. The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of AD, and previous reports have demonstrated that the blockade of glutamate receptors prevents Abeta-induced neuronal death. We show that taurine, a beta-amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate receptor agonists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demonstrated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABA(A) receptors. GABA and the GABA(A) receptor agonists phenobarbital and melatonin also protect neurons against Abeta-induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may represent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.
Assuntos
Precursor de Proteína beta-Amiloide/toxicidade , Proteínas do Olho/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de GABA/efeitos dos fármacos , Receptores de Glutamato/efeitos dos fármacos , Taurina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Células Cultivadas , Senescência Celular , Embrião de Galinha , Maleato de Dizocilpina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Proteínas do Olho/fisiologia , Ácido Glutâmico/farmacologia , Ácido Caínico/toxicidade , N-Metilaspartato/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Picrotoxina/farmacologia , Receptores de AMPA/efeitos dos fármacos , Receptores de GABA/fisiologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Receptores de Glutamato/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Retina/citologia , Retina/embriologia , Taurina/uso terapêutico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaAssuntos
Humanos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/toxicidade , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genéticaRESUMO
Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß) peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease