Articolo in rivista, 2012, ENG, 10.3389/fncom.2012.00052

Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments

Culmone V; Migliore M

CNR, Inst Biophys, I-90146 Palermo, Italy; Univ Palermo, Dept Math & Informat, Palermo, Italy

Several independent studies show that accumulation of ?-amyloid (A?) 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 A? 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 A?. 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.

Frontiers in computational neuroscience 6 , pp. 1–9

Keywords

A?-peptide, hippocampal neuron, realistic model, ion channels modulation

CNR authors

Migliore Michele

CNR institutes

IBF – Istituto di biofisica

ID: 195942

Year: 2012

Type: Articolo in rivista

Creation: 2012-12-18 17:16:17.000

Last update: 2012-12-18 17:16:17.000

CNR authors

External IDs

CNR OAI-PMH: oai:it.cnr:prodotti:195942

DOI: 10.3389/fncom.2012.00052

ISI Web of Science (WOS): 000306605600001