A New Target for Amyloid Beta Toxicity Validated by Standard and High-Throughput Electrophysiology

Abstract

BackgroundSoluble oligomers of amyloid beta (Aβ) are considered to be one of the major contributing factors to the development of Alzheimer's disease. Most therapeutic development studies have focused on toxicity directly at the synapse.Methodology/Principal FindingsPatch clamp studies detailed here have demonstrated that soluble Aβ can also cause functional toxicity, namely it inhibits spontaneous firing of hippocampal neurons without significant cell death at low concentrations. This toxicity will eventually lead to the loss of the synapse as well, but may precede this loss by a considerable amount of time. In a key technological advance we have reproduced these results utilizing a fast and simple method based on extracellular electrophysiological recording of the temporal electrical activity of cultured hippocampal neurons using multielectrode arrays (MEAs) at low concentrations of Aβ (1–42). We have also shown that this functional deficit can be reversed through use of curcumin, an inhibitor of Aβ oligomerization, using both analysis methods.Conclusions/SignificanceThe MEA recording method utilized here is non-invasive, thus long term chronic measurements are possible and it does not require precise positioning of electrodes, thus it is ideal for functional screens. Even more significantly, we believe we have now identified a new target for drug development for AD based on functional toxicity of hippocampal neurons that could treat neurodegenerative diseases prior to the development of mild cognitive impairment.

Abeta(1-42) Enhances Neuronal Excitability in the CA1 via NR2B Subunit-Containing NMDA Receptors

“…Similar results have been recently reported by Varghese et al using cultured embryonic rat hippocampal cells. Abeta increased spontaneous firing activity dose dependently, reaching the maximum after 1 hour of treatment, which was followed by a complete cessation of spikes following a few hours [42]. The discrepancy between this and our result may be due to the fact that the authors have used a cell culture largely devoid of glial elements, while we have used a complex microcircuitry built up from all of the neuronal cell types (including glia) forming elaborate connections.…”

A phenotypic in vitro model for the main determinants of human whole heart function

“…Application of patient-derived human cardiomyocytes (from induced pluripotent stem cell sources) in the system would open new avenues in drug testing, targeting disease state modeling or individual genetic variability in the patient population. Integration of this system with other constructs, such as physiologically correct functional systems for skeletal muscle[31], neuromuscular junctions[48], myelination[46] and neuronal networks[49], modeling different tissue functions would be straightforward.…”

Immunomodulatory and therapeutic activity of curcumin

“…Amyloid plaque burden has been associated with depolarizing of the neuronal membrane and enhanced glutamate-mediated excitotoxicity [138,139] that results in impaired electrical firing of the neurons. Curcumin administration has been shown to prevent misfiring of neurons following Aβ burden in embryonic hippocampal neurons [140]. In nitrosourea induced neurotoxicity, curcumin administration prevented increase in the activity of glucose metabolic pathway enzymes including hexokinase, LDH and SDH [141].…”