Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments
- 1Institute of Biophysics, National Research Council, Palermo, Italy
- 2Department of Mathematics and Informatics, University of Palermo, Palermo, Italy
Several independent studies show that accumulation of β-amyloid (Aβ) peptides, one of the characteristic hallmark of Alzheimer's Disease (AD), can affect normal neuronal activity in different ways. However, in spite of intense experimental work to explain the possible underlying mechanisms of action, a comprehensive and congruent understanding is still lacking. Part of the problem might be the opposite ways in which Aβ have been experimentally found to affect the normal activity of a neuron; for example, making a neuron more excitable (by reducing the A- or DR-type K+ currents) or less excitable (by reducing synaptic transmission and Na+ current). The overall picture is therefore confusing, since the interplay of many mechanisms makes it difficult to link individual experimental findings with the more general problem of understanding the progression of the disease. This is an important issue, especially for the development of new drugs trying to ameliorate the effects of the disease. We addressed these paradoxes through computational models. We first modeled the different stages of AD by progressively modifying the intrinsic membrane and synaptic properties of a realistic model neuron, while accounting for multiple and different experimental findings and by evaluating the contribution of each mechanism to the overall modulation of the cell's excitability. We then tested a number of manipulations of channel and synaptic activation properties that could compensate for the effects of Aβ. The model predicts possible therapeutic treatments in terms of pharmacological manipulations of channels' kinetic and activation properties. The results also suggest how and which mechanisms can be targeted by a drug to restore the original firing conditions.
Keywords: Aβ-peptide, hippocampal neuron, realistic model, ion channels modulation
Citation: Culmone V and Migliore M (2012) Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments. Front. Comput. Neurosci. 6:52. doi: 10.3389/fncom.2012.00052
Received: 05 March 2012; Accepted: 05 July 2012;
Published online: 23 July 2012.
Copyright © 2012 Culmone and Migliore. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Michele Migliore, Institute of Biophysics, National Research Council, via Ugo La Malfa 153, 90146 Palermo, Italy. e-mail: firstname.lastname@example.org