Early Alterations of Hippocampal Neuronal Firing Induced by Abeta42

We studied the effect of Amyloid β 1-42 oligomers (Abeta42) on Ca²⁺ dependent excitability profile of hippocampal neurons. Abeta42 is one of the Amyloid beta peptides produced by the proteolytic processing of the amyloid precursor protein and participates in the initiating event triggering the progressive dismantling of synapses and neuronal circuits. Our experiments on cultured hippocampal network reveal that Abeta42 increases intracellular Ca²⁺ concentration by 46% and inhibits firing discharge by 19%. More precisely, Abeta42 differently regulates ryanodine (RyRs), NMDA receptors (NMDARs), and voltage gated calcium channels (VGCCs) by increasing Ca²⁺ release through RyRs and inhibiting Ca²⁺ influx through NMDARs and VGCCs. The overall increased intracellular Ca²⁺ concentration causes stimulation of K⁺ current carried by big conductance Ca²⁺ activated potassium (BK) channels and hippocampal network firing inhibition. We conclude that Abeta42 alters neuronal function by means of at least 4 main targets: RyRs, NMDARs, VGCCs, and BK channels. The development of selective modulators of these channels may in turn be useful for developing effective therapies that could enhance the quality of life of AD patients during the early onset of the pathology.

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