Research article

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

Lana Shabala^*, Claire Howells, Adrian K West and Roger S Chung

• * Corresponding author: Lana Shabala L.Shabala@utas.edu.au

Author Affiliations

NeuroRepair Group, Menzies Research Institute, University of Tasmania. Private Bag 23, Hobart, Tasmania, 7001, Australia

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Molecular Neurodegeneration 2010, 5:30 doi:10.1186/1750-1326-5-30

Published: 13 August 2010

Abstract

Background

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterised by the formation of insoluble amyloidogenic plaques and neurofibrillary tangles. Beta amyloid (Aβ) peptide is one of the main constituents in Aβ plaques, and is thought to be a primary causative agent in AD. Neurons are likely to be exposed to chronic, sublethal doses of Aβ 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 μM of Aβ_1-40 over 7 days and compared their survival with age-similar untreated cells. We also investigated whether chronic Aβ exposure affects neuronal susceptibility to the subsequent acute excitotoxicity induced by 10 μM glutamate and assessed how Ca²⁺ and K⁺ homeostasis were affected by either treatment.

Results

We show that continuous exposure to 1 μM Aβ_1-40 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 μM Aβ 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 Aβ 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 Aβ treatment with 2.5-fold increase in total Ca²⁺ uptake over 20 min post glutamate application after six days of Aβ treatment or longer (P < 0.05).

Conclusions

Our data suggest that long term exposure to Aβ 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 Aβ.