Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: Implications for depression and Alzheimer's disease

Abstract

The relationship between Alzheimer's disease (AD) and depression has been well established in terms of epidemiological and clinical observations. Depression has been considered to be both a symptom and risk factor of AD. Several genetic and neurobiological mechanisms have been described to underlie these two disorders. Despite the accumulating knowledge on this topic, the precise neuropathological mechanisms remain to be elucidated. In this study, we propose that synaptic degeneration plays an important role in the disease progression of depression and AD. Using primary culture of hippocampal neurons treated with oligomeric Aβ and corticosterone as model agents for AD and depression, respectively, we found significant changes in the pre-synaptic vesicle proteins synaptophysin and synaptotagmin. We further investigated whether the observed protein changes affected synaptic functions. By using FM(®)4-64 fluorescent probe, we showed that synaptic functions were compromised in treated neurons. Our findings led us to investigate the involvement of protein degradation mechanisms in mediating the observed synaptic protein abnormalities, namely, the ubiquitin-proteasome system and autophagy. We found up-regulation of ubiquitin-mediated protein degradation, and the preferential signaling for the autophagic-lysosomal degradation pathway. Lastly, we investigated the neuroprotective role of different classes of antidepressants. Our findings demonstrated that the antidepressants Imipramine and Escitalopram were able to rescue the observed synaptic protein damage. In conclusion, our study shows that synaptic degeneration is an important common denominator underlying depression and AD, and alleviation of this pathology by antidepressants may be therapeutically beneficial.

H<sub>2</sub>S protects PC12 cells against toxicity of corticosterone by modulation of BDNF-TrkB pathway

“…Taken together, our data demonstrated the protective role of H 2 S against the neurotoxicity of corticosterone. It was reported that the neurotoxicity of corticosterone plays an important role in the development of depression [14,15]. In addition, our recent studies have shown that H 2 S has antidepressant-like effect [25,26].…”

“…Moreover, chronic corticosterone exposure induces neuronal damage in hippocampus [10] and depressive-like behavior in animal model [11], apoptosis and injury of PC12 cells in vitro [12,13]. Interestingly, corticosterone can cause synaptic degeneration and exert toxic effects on hippocampal neurons, and finally induces depression [14]. It is also well-known that corticosterone exposure induces a decrease in dendritic spine density in hippocampus, which might be one of the pathophysiological mechanisms underlying depression progression [15].…”

Protective Effects of Testosterone on Presynaptic Terminals against Oligomericβ-Amyloid Peptide in Primary Culture of Hippocampal Neurons

“…Primary cultures of rat hippocampal neurons were prepared from embryonic day 18 Sprague-Dawley rat embryos by using the method described previously [28]. Briefly, hippocampi were dissected in 1X PBS supplemented with glucose (18 mM).…”

“…The working concentration of A β was 5  μ M in all experiments. This concentration of A β could induce synaptic degeneration including the reduction of synaptic proteins but not apoptosis when applied to hippocampal neurons for 24 h [28, 31]. …”

M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

“…Synaptic degeneration is suggested to be closely connected to the pathogenesis of depression, resulting from a significant loss of pre- and post-synaptic proteins [55, 56]. Pre-synaptic vesicle proteins play a role in the release of neurotransmitter into the synaptic cleft facilitating the neuronal communication while post-synaptic proteins orchestra the received pre-synaptic signal that in turn to adjust and fine-tune the activity of the dendritic spine [57, 58].…”