Prolonged Aβ treatment leads to impairment in the ability of primary cortical neurons to maintain K+ and Ca2+ homeostasis
| Autor: | Adrian K. West, Claire Howells, Lana Shabala, Roger S. Chung |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
medicine.medical_specialty
Amyloid Central nervous system Excitotoxicity Clinical Neurology Physiology lcsh:Geriatrics medicine.disease_cause lcsh:RC346-429 Pathogenesis 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Internal medicine Medicine Molecular Biology lcsh:Neurology. Diseases of the nervous system 030304 developmental biology 0303 health sciences business.industry Glutamate receptor Molecular medicine In vitro 3. Good health lcsh:RC952-954.6 Endocrinology medicine.anatomical_structure Neurology (clinical) business 030217 neurology & neurosurgery Homeostasis Research Article |
| Zdroj: | Molecular Neurodegeneration, Vol 5, Iss 1, p 30 (2010) Molecular Neurodegeneration |
| ISSN: | 1750-1326 |
| DOI: | 10.1186/1750-1326-5-30 |
| Popis: | 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 Aβ1-40 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 Aβ1-40 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. |
| Databáze: | OpenAIRE |
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