Mechanisms of synaptic pathology in Alzheimer's disease

Neurodegenerative disorders are characterized by damage to selective neuronal populations that could be followed or preceded by synaptic injury. Therefore, specific mutations in and other alterations of synaptic proteins might lead to particular neurodegenerative diseases. The predominant hypothesis is that these mutations result in an increased production of amyloid beta-protein 1-42 which acts as a neurotoxin. However, it could also be postulated that amyloid precursor protein might play an important role in synaptic function and neuronal maintenance and that its abnormal activity may lead to neurodegeneration. Recent studies have shown that amyloid precursor protein has an important role in regulating glutamate levels at the synaptic site by modulating the activity of glutamate transporters. The objectives of this manuscript are to highlight recent data supporting the hypothesis that neurodegeneration in Alzheimer's disease might be the combined result of abnormal protective activity of amyloid precursor protein and amyloid beta-protein toxicity.