Kinetic modeling of amyloid fibrillation and synaptic plasticity as memory loss and formation mechanisms

[摘要] (cont.) First, presynaptic vesicle trafficking that leads to the release of glutamate as neurotransmitter was taken into account to explain short-term plasticity data. Second, long-term plasticity data lasting for hours after tetanus stimuli has been matched by a calcium entrapment model we developed. Model differentiation was done to demonstrate the better performance of calcium entrapment model than an alternative bistable theory in fitting graded long-term potentiation responses. Finally, to decipher spike timing dependent plasticity (STDP), we developed a systematic model incorporating back propagation of action potential, dual requirement of NMDA receptors, and calcium dependent plasticity. This built model is supported by five different types of STDP experimental data. The accumulation of amyloid beta has been found to disrupt the sustainable modification of long-term synaptic plasticity which might explain the inability of AD patients to form new memory at early stage of the disease. Yet the linkage between the existence of amyloid beta species and failure of long-term plasticity was unclear. We suggest that the abnormality of calcium entrapment function caused by amyloid oligomers is the intermediate step that eventually leads to memory loss. Unsustainable calcium level and decreased postsynaptic activities result into the removal or internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The number of AMPA receptors as the indicators of synaptic strength may result into disconnection between neurons and even neuronal apoptosis. New experiments have been suggested to validate this hypothesis and to elucidate the pathology of Alzheimer;;s disease.

[发布机构] Massachusetts Institute of Technology