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

Suthicha Wuwongse, Sally Shuk Yee Cheng, Ginger Tsz Hin Wong, Clara Hiu Ling Hung, Natalie Qishan Zhang, Yuen Shan Ho, Andrew Chi Kin Law, Raymond Chuen Chung Chang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

27 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2245-2256
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number12
DOIs
Publication statusPublished - 1 Dec 2013
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Antidepressant
  • Depression
  • Synaptophysin
  • Synaptotagmin
  • Ubiquitin proteasome system

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this