RESUMO
Amyloid beta (Abeta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD). As a result of conformational changes, Abeta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alphaB-crystallin and Hsp27 occur at increased levels and colocalize with these plaques. In vitro, sHsps act as molecular chaperones that recognize unfolding peptides and prevent their aggregation. The presence of sHsps in AD brains may thus reflect an attempt to prevent amyloid fibril formation and toxicity. Here we report that alphaB-crystallin does indeed prevent in vitro fibril formation of Abeta(1-40). However, rather than protecting cultured neurons against Abeta(1-40) toxicity, alphaB-crystallin actually increases the toxic effect. This indicates that the interaction of alphaB-crystallin with conformationally altering Abeta(1-40) may keep the latter in a nonfibrillar, yet highly toxic form.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Cristalinas/farmacologia , Chaperonas Moleculares/farmacologia , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Placa Amiloide/efeitos dos fármacos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Benzotiazóis , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral , Relação Dose-Resposta a Droga , Hipocampo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Ligação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína/efeitos dos fármacos , Ratos , TiazóisRESUMO
We used primary cultures of rat hippocampal tissue to estimate the contribution of anion exchange (AE) proteins to the regulation of intracellular pH in neurones and astrocytes. After induction of acidosis, neonatal rat astrocytes were able to restore the intracellular pH in the absence of extracellular bicarbonate. Neonatal neurones, however, were able to recover from acidosis only when bicarbonate was present in the extracellular medium. This recovery was inhibited by inhibition of anion exchange and was independent of the presence of sodium ions. Antibodies against AE proteins reacted predominantly with neurones. These data suggest that neurones in particular are dependent on functional AE proteins for the maintenance of their intracellular pH.