RESUMO
Amyloid-beta protein (Abeta) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of Abeta and its physiological role in non-disease states is not clear. In these studies, low doses of Abeta enhanced memory retention in two memory tasks and enhanced acetylecholine production in the hippocampus in vivo. We then tested whether endogenous Abeta has a role in learning and memory in young, cognitively intact mice by blocking endogenous Abeta in healthy 2-month-old CD-1 mice. Blocking Abeta with antibody to Abeta or DFFVG (which blocks Abeta binding) or decreasing Abeta expression with antisense directed at the Abeta precursor, AbetaPP, all resulted in impaired learning in T-maze foot-shock avoidance. Finally, Abeta 1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to Abeta inhibited hippocampal LTP. In conclusion, these results indicate that in normal healthy young animals the presence of Abeta is important for learning and memory.
Assuntos
Peptídeos beta-Amiloides/fisiologia , Aprendizagem em Labirinto/fisiologia , Reconhecimento Psicológico/fisiologia , Acetilcolina/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/farmacologia , Análise de Variância , Animais , Anticorpos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Relação Dose-Resposta a Droga , Técnicas Eletroquímicas/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Microdiálise/métodos , Testes Neuropsicológicos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Fatores de TempoRESUMO
Decreased clearance is the main reason amyloid-beta protein (Abeta) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Abeta at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Abeta42, increased brain levels of Abeta42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Abeta could increase and AD would be promoted.