| A major ongoing effort in the Cellular and Molecular Neuroscience Unit is to understand events occurring in synaptic terminals that may lead to dysfunction and degeneration of neurons during aging and age-related diseases. This diagram shows one example where the amyloid precursor protein is enzymatically processed in presynaptic terminals in several different ways. One processing pathway, which is stimulated by electrical activity in neurons, results in release of a secreted form of APP, sAPPa, which activates postsynaptic receptors linked to cyclic GMP production, and activation of potassium channels which hyper-polarizes the membrane; cyclic GMP also activates the transcription factor NF-kB. The enzyme responsible for production of sAPPa is called a-secretase, and this enzyme cleaves APP in the middle of the amyloid b-peptide sequence, thereby precluding production of neurotoxic Ab. It is believed that this sAPPa -generating pathway is involved in modulating synaptic plasticity in processes such as learning and memory and that it may also provide a mechanism for suppressing excitability and protecting neurons against excitotoxicity. Alternative processing of APP in synaptic terminals by b and g secretases, which occurs at the membrane and in intracellular compartments (golgi and endosomal/lysosomal vesicles), result in production of amyloid b-peptide which then may be released from cells, aggregate, and then impair the function of synapses and promote neuronal degeneration. |
