抄録
The senile plaque, extracellular deposit of amyloid-β (Aβ), is a pathological hallmark of Alzheimer's disease (AD). Recent studies have shown that Aβ, prior to accumulating extracellularly, is increased first intracellularly and may trigger neuronal dysfunction especially in the early stage of AD. We attempted to study the functional role of intracellular Aβ, by introducing Aβ protein into pyramidal neurons through patch pipettes in rat neocortical slices. With Aβ intracellularly injected, spike-induced Ca2+ increases, measured with fura-2-based fluorimetry, were greater than control. However, neither did Aβ injection alter Ca2+ current under voltage clamp nor cause Ca2+ release from intracellular Ca2+ stores. Instead, Aβ enlarged the spike width by suppressing large conductance Ca2+-activated potassium channels, thus increasing spike-induced Ca2+ influx. Given that the formation and secretion of Aβ have been shown to depend on neural activity, the present Aβ-promoted elevation of neural excitability can lead to a positive feedback increase in production of intracellular Aβ. Such self-reinforceing increase in intracellular Aβ may well rise extracellular Aβ, thus triggering further pathological changes such as synaptic dysfunction and neuronal loss. We propose that in the early stage of AD, intracellular increase in Aβ may render neurons more vulnerable to cell death and could be causative of the disease. [J Physiol Sci. 2008;58 Suppl:S126]
