Molecular Medicine (May 2018)

Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

  • Xin-Rui Han,
  • Xin Wen,
  • Yong-Jian Wang,
  • Shan Wang,
  • Min Shen,
  • Zi-Feng Zhang,
  • Shao-Hua Fan,
  • Qun Shan,
  • Liang Wang,
  • Meng-Qiu Li,
  • Bin Hu,
  • Chun-Hui Sun,
  • Dong-Mei Wu,
  • Jun Lu,
  • Yuan-Lin Zheng

DOI
https://doi.org/10.1186/s10020-018-0020-y
Journal volume & issue
Vol. 24, no. 1
pp. 1 – 12

Abstract

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Abstract Background As a form of dementia primarily affecting the elderly, vascular dementia (VD) is characterized by changes in the supply of blood to the brain, resulting in cognitive impairment. The aim of the present study was to explore the effects involved with cyclic adenosine monophosphate (cAMP) response element-binding (CREB)1 gene silencing on cognitive dysfunction through meditation of the protein kinase A (PKA)-CREB signaling pathway in mice with VD. Methods Both the Morris water maze test and the step down test were applied to assess the cognitive function of the mice with VD. Immunohistochemical and TUNEL staining techniques were employed to evaluate the positive expression rates of the protein CREB1 and Cleaved Caspase-3, as well as neuronal apoptosis among hippocampal tissues in a respective manner. Flow cytometry was applied to determine the proliferation index and apoptosis rate of the hippocampal cells among each group. Reverse transcription quantitative polymerase chain reaction and Western blot analysis methods were applied to detect the expressions of cAMP, PKA and CREB in hippocampal cells. Results Compared with the normal group, all the other groups exhibited impaired cognitive function, reduced cell numbers in the CAI area, positive expressions of CREB1 as well as positive optical density (OD) values. Furthermore, increased Cleaved Caspase-3 positive expression, OD value, proliferation index, apoptosis rate of hippocampal cells and neurons, were observed in the other groups when compared with the normal group, as well as lower expressions of cAMP, PKA and CREB1 and p-CREB1 (the shCREB1–1, H89 and shCREB1–1 + H89 groups < the VD group). Conclusion The key findings of the present study demonstrated that CREB1 gene silencing results in aggravated VD that occurs as a result of inhibiting the PKA-CREB signaling pathway, thus exasperating cognitive dysfunction.

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