Altered ion channel expression as a mechanism of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia. The main pathological hallmark associated with the disease is the presence of senile plaques that are composed of amyloid beta peptide (Aβ). This peptide is a key component in disease pathology and is thought to underlie neuronal loss seen in AD brains. Recent evidence now suggests a physiological role for the peptide in the maintenance of neuronal excitability. At physiological concentrations of Aβ (10 nM), we have previously demonstrated the modulation of Kv4.2 channels. In the present study we investigated both the physiological and the pathological concentrations of Aβ that contains 40 amino acid residues (Aβ 1-40), and determined its effects on Kv4.2 channels. Aβ1-40 was toxic to cerebellar granule neurons at a concentration of 1 μM and above, therefore this concentration was used to examine pathological effects. Physiological effects were examined using 10 nM Aβ1-40 . Significant reductions in A-type K+ channel current in hippocampal and cerebellar granule neurons was observed at 1μM, in a Ca2+ dependent manner. Cellular localisation of Kv4.2 was determined using immunofluorescence Aβ1-40 reduced both Kv4.2 and postsynaptic density 95 (PSD-95), at hippocampal dendrites at 1μ M. At 10 nM, Kv4.2 channel expression was increased independently of PSD-95. In Kv4.2 overexpressing cell lines, Aβ1-40 had no modulatory effect at the pathological concentration. The data presented herein demonstrate a reduction in K" channel current in neurons in response to soluble Aβ1-40 (1 μM). Furthermore, we show a modulatory effect of Aβ1 -40 on Kv4.2 expression in hippocampal dendrites at both pathological and physiological concentrations. PSD-95 expression was only co-modulated at the pathological concentrations, indicating divergent mechanisms dependent on the v concentrations of Aβ1-40 used. The loss of Kv4.2 and PSO-95 at 1μM Aβ1-40 could possibly correlate with early synaptic dysfunction in Alzheimer's DiseaseEThOS - Electronic Theses Online ServiceGBUnited Kingdo