Title

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

Authors

Authors

K. Varghese; P. Molnar; M. Das; N. Bhargava; S. Lambert; M. S. Kindy;J. J. Hickman

Comments

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Abbreviated Journal Title

PLoS One

Keywords

LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; MICROELECTRODE ARRAYS; NEURONAL NETWORKS; MULTIELECTRODE ARRAYS; HIPPOCAMPAL-NEURONS; SYNAPTIC; ACTIVITY; DEFINED SYSTEM; OLIGOMERS; MECHANISMS; Multidisciplinary Sciences

Abstract

Background: Soluble oligomers of amyloid beta (A beta) 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 Findings: Patch clamp studies detailed here have demonstrated that soluble A beta 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 A beta (1-42). We have also shown that this functional deficit can be reversed through use of curcumin, an inhibitor of A beta oligomerization, using both analysis methods. Conclusions/Significance: 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.

Journal Title

Plos One

Volume

5

Issue/Number

1

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

8

WOS Identifier

WOS:000273414200020

ISSN

1932-6203

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