Affiliations: Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, UMass Lowell, Lowell, MA, USA
Correspondence:
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Correspondence to: Thomas B. Shea, Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, UMass Lowell, Lowell, MA 01854, USA. Tel.: +1 978 934 2881; E-mail: thomas_Shea@uml.edu.
Note: [1] These authors contributed equally to this research.
Abstract: Alzheimer's disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm–5 μM) of human Aβ1-42 perturbed synaptic transmission within hours. This perturbation suggests that mild cognitive problems, perhaps undetected by traditional clinical approaches, can accompany critical accumulation of Aβ. This effect was prevented by the calcium chelator BAPTA, indicating a requirement for calcium for inhibition of signaling by Aβ. Aβ-induced inhibition of signaling was not prevented by application of MK-801 or nimodipine (antagonists of the NMDA receptor and L-type voltage-sensitive calcium channel, respectively) suggesting that Aβ may induce influx by either channel, or additional channels, or that neurons contained sufficient calcium to mediate the impact of Aβ. Signaling returned to original levels within 120 h after administration of a single dosage of Aβ, or within 24 h after replacement of medium with fresh medium lacking Aβ, suggesting that intervention to reduce Aβ levels at their first appearance may prevent permanent neurotoxicity.
