RETRACTED ARTICLE: Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia

Abstract

BackgroundAs 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.MethodsBoth 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.ResultsCompared 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).ConclusionThe 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.

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

“…The prevailing view of the cAMP‐PKA‐CREB signaling pathway is closely related to cognitive deficits . Several mechanisms for this have been proposed, including the regulation by γ‐aminobutyric acid‐B receptor, regulation of transcription factor myocyte‐enhancer factor 2, activation downstream of NF‐kB signaling pathway and related proinflammatory cytokines, increased downstream of proapoptotic proteins (Bcl‐2 family and caspase) expression, and reduction of BDNF expression .…”

“…Neuronal apoptosis is considered to be one of the mechanisms of Mn‐induced neurotoxicity, which involves Bcl‐2 family‐mediated mitochondrial dysfunction, cytochrome c release, and caspases' activation . Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function . As a second messenger of intracellular signal, cAMP can activate PKA, which can lead to phosphorylation of CREB (pCREB) on Ser133 .…”

“…These processes have been demonstrated as important for the induction and persistence of long‐term memory and long‐term potentiation . In addition, the pCREB can also regulate the expression of downstream apoptosis‐associated proteins, including Bcl‐2, Bax, caspase‐3, caspase‐8, and brain‐derived neurotrophic factor (BDNF), which have been found to promote the apoptosis of neurons, and share an association with aggravating cognitive dysfunction . Our previous studies showed that Mn exposure impaired hippocampus‐dependent cognitive function and reduced cAMP signaling and the protein levels of BDNF in occupational Mn‐exposed workers and chronic Mn‐treated rats .…”

“…20,21 In addition, the pCREB can also regulate the expression of downstream apoptosis-associated proteins, including Bcl-2, Bax, caspase-3, caspase-8, and brain-derived neurotrophic factor (BDNF), 19,[22][23][24] which have been found to promote the apoptosis of neurons, and share an association with aggravating cognitive dysfunction. 15,25 Our previous studies showed that Mn exposure impaired hippocampus-dependent cognitive function and reduced cAMP signaling and the protein levels of BDNF in occupational Mn-exposed workers and chronic Mn-treated rats. 26,27 Nevertheless, the precise mechanism through the cAMP signaling pathway in Mn-induced neurotoxicity is still not completely understood.…”

“…12,13 Recent evidence suggests that cAMP-PKA-CREB signaling regulates apoptosis and is associated with cognitive function. [14][15][16][17] As a second messenger of intracellular signal, cAMP can activate PKA, which can lead to phosphorylation of CREB (pCREB) on Ser133. 18,19 These processes have been demonstrated as important for the induction and persistence of long-term memory and long-term potentiation.…”