Prolonged Abeta treatment leads to impairment in the ability of primary cortical neurons to maintain K+ and Ca2+ homeostasis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterised by the formation of insoluble amyloidogenic plaques and neurofibrillary tangles. Beta amyloid (Abeta) peptide is one of the main constituents in Abeta plaques, and is thought to be a primary causative agent in AD. Neurons are likely to be exposed to chronic, sublethal doses of Abeta over an extended time during the pathogenesis of AD, however most studies published to date using in vitro models have focussed on acute studies. To experimentally model the progressive pathogenesis of AD, we exposed primary cortical neurons daily to 1 muM of Abeta1-40 over 7 days and compared their survival with age-similar untreated cells. We also investigated whether chronic Abeta exposure affects neuronal susceptibility to the subsequent acute excitotoxicity induced by 10 muM glutamate and assessed how Ca2+ and K+ homeostasis were affected by either treatment.

Results: We show that continuous exposure to 1 muM Abeta1-40 for seven days decreased survival of cultured cortical neurons by 20%. This decrease in survival correlated with increased K+ efflux from the cells. One day treatment with 1 muM Abeta followed by glutamate led to a substantially higher K+ efflux than in the age-similar untreated control. This difference further increased with the duration of the treatment. K+ efflux also remained higher in Abeta treated cells 20 min after glutamate application leading to 2.8-fold higher total K+ effluxed from the cells compared to controls. Ca2+ uptake was significantly higher only after prolonged Abeta treatment with 2.5-fold increase in total Ca2+ uptake over 20 min post glutamate application after six days of Abeta treatment or longer (P < 0.05).

Conclusions: Our data suggest that long term exposure to Abeta is detrimental because it reduces the ability of cortical neurons to maintain K+ and Ca2+ homeostasis in response to glutamate challenge, a response that might underlie the early symptoms of AD. The observed inability to maintain K+ homeostasis might furthermore be useful in future studies as an early indicator of pathological changes in response to Abeta.