A new target for amyloid beta toxicity validated by standard and high-throughput electrophysiology.
BACKGROUND
Soluble oligomers of amyloid beta (Abeta) 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.


RESULTS
Patch clamp studies detailed here have demonstrated that soluble Abeta 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 Abeta (1-42). We have also shown that this functional deficit can be reversed through use of curcumin, an inhibitor of Abeta oligomerization, using both analysis methods.


CONCLUSIONS
The 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.
Varghese
Kucku
K
NanoScience Technology Center, University of Central Florida, Orlando, Florida, United States of America.
Molnar
Peter
P
Das
Mainak
M
Bhargava
Neelima
N
Lambert
Stephen
S
Kindy
Mark S
MS
Hickman
James J
JJ
D000200:Action Potentials; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D003474:Curcumin / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods*; D051381:Rats; D013569:Synapses / Q000502:physiology
D016229:Amyloid beta-Peptides; D003474:Curcumin