Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: implications for depression and Alzheimer's disease.
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.
Neurodysfunction Research Laboratory, Department of Psychiatry, LKS Faculty of Medicine, Hong Kong, China; Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, Hong Kong, China.
Suthicha
S
Wuwongse
Sally Shuk-Yee
SS
Cheng
Ginger Tsz-Hin
GT
Wong
Clara Hiu-Ling
CH
Hung
Natalie Qishan
NQ
Zhang
Yuen-Shan
YS
Ho
Andrew Chi-Kin
AC
Law
Raymond Chuen-Chung
RC
Chang
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001343:Autophagy; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; C569014:SYP protein, human; D016708:Synaptophysin; D025801:Ubiquitin; D050857:Synaptotagmins; D046988:Proteasome Endopeptidase Complex; D003345:Corticosterone
AD; Alzheimer's disease; Antidepressant; Aβ; CORT; Depression; E1; E2; E3; HPA; NFT; PSD95; Synaptophysin; Synaptotagmin; Ubiquitin proteasome system; corticosterone; hypothalamic–pituitary–adrenal; neurofibrillary tangles; post-synaptic density 95; ubiquitin activating enzymes; ubiquitin conjugating enzymes; ubiquitin ligases; β-amyloid