Synaptic vesicle protein pathology in alzheimer's disease and depression

Abstract

BACKGROUND: Neuropsychiatric symptoms are common amongst Alzheimer’s disease (AD) patients. Apart from cognitive decline, AD patients often present with depression and psychosis; however, the neurobiological processes underlying these associating conditions remain unclear. Chemical synaptic transmission is crucial in the communication between neurons, and ultimately brain function. We propose synaptic dysfunction as a possible underlying mechanism for AD and depression. Furthermore, since synaptic degeneration is likely to be a relatively early pathological event, we investigated the potential neuroprotective role of antidepressants. METHODS: Primary hippocampal neurons treated with either oligomeric ß-amyloid (Aß) or corticoster one were used as an in vitro model for AD and depression, respectively. Immunocytochemical analyses of synaptic vesicle proteins were employed to investigate the pathological changes. RESULTS: Sub-lethal dosage of Aß (0.5mM) treatment for 24 hours resulted in reduction of presynaptic vesicle proteins synaptotagmin and synaptophysin. Pre-treatment for hour with antidepressants -- either imipramine or escitalopram (10mM and 20mM for both) -- were able to alleviate these pathological changes. Sub-lethal dosage of corticoster one (0.5mM) treatment for 24 hours resulted in aggregation of pre-synaptic vesicle proteins synaptotagmin and synaptophysin. Pre-treatments for hour with imipramine (10mM and 20mM) were able to alleviate these pathological changes. Pre-treatments for hour with escitalopram (10mM and 20mM) were only able to alleviate the aggregation of synaptotagmin, but not synaptophysin. CONCLUSIONS: These results show synaptic protein loss or aggregation in in vitro models of AD and depression. Antidepressants were able to alleviate some of the observed pathological changes. Further experiments will be conducted to explore the functional implications of these pathologies and the differential responses towards antidepressant treatments.