PI3K/Akt Signal Pathway Involved in the Cognitive Impairment Caused by Chronic Cerebral Hypoperfusion in Rats

Abstract

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological state that usually occurs in conditions such as vascular dementia and Alzheimer's disease, both of which are characterized by cognitive impairment. In previous studies we found that learning capacity and memory were gradually impaired with CCH, which altered the expression of synaptophysin, microtubule associated protein-2, growth associated protein-43, brain-derived neurotrophic factor, nerve growth factor, N-methyl-D-aspartate receptor subunit 1, cAMP response element-binding protein and tau hyperphosphorylation in the hippocampus. However, the molecular basis of cognitive impairment in CCH remains obscure. Here we explore the hypothesis that the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signal pathway is involved in this type of cognitive impairment. In order to determine if the expression of PI3K, Akt and phosphorylated Akt (p-Akt) proteins are altered at different stages of CCH with differing levels of cognitive impairment. we performed permanent, bilateral occlusion of the common carotid arteries (2-VO) to induce CCH. Adult male SD rats were randomly divided into sham-operated group, 2-VO 1 week group, 2-VO 4 weeks group and 2-VO 8 weeks group. Behavior tests were utilized to assess cognitive abilities, while western blots were utilized to evaluate protein expression. Rats in the 2-VO groups spent less time exploring novel objects than those in the sham-operated group, and the discrimination ratio of the 2-VO 8 weeks group and the sham-operated group were higher than chance (0.50). Escape latencies in the Morris water maze task in the 2-VO 1 week group were longer than those in the sham-operated group on day 4 and day 5, while escape latencies in the 2-VO 4 weeks group were longer than those in the sham-operated group from day 3 to day 5. Escape latencies in 2-VO 8 weeks group were longer than those in the sham-operated group from day 2 to day 5. NE (northeast) square swimming times in the 2-VO 1 week group, 2-VO 4 weeks group and 2-VO 8 weeks group were shorter than that in the sham-operated group. Western blotting showed that the PI3K expression in the 2-VO 1 week group was lower than that in sham-operated group, while p-Akt expression in the 2-VO 8 weeks group was higher than that in the sham-operated group. There was a linear relationship between the PI3K expression and the discrimination ratio, as well as a linear relationship between the PI3K and NE square swimming time. Thus, we propose that the PI3K/Akt signal pathway is an important cell pathway that is associated with the cognitive impairment following CCH.

Brain BDNF levels are dependent on cerebrovascular endothelium‐derived nitric oxide

“…Given that cognition is improved by short‐term physical exercise (Vaynman et al ., ) and deficient at day 10 after 2VO induction (Shu et al ., ; Damodaran et al ., ), the most surprising and unexpected result of this study was that both EX and 2VO resulted in an increase in brain p‐TrkB tyr816 levels. These data raise questions about the reliability of the measurement of brain p‐TrkB tyr816 levels to explore BDNF‐dependent neuroplasticity in rats subjected to 2VO, and raise the possibility that cellular pathways downstream from surface and/or internalized p‐TrkB tyr816 receptors are impaired in 2VO rats.…”

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

“…AKT signaling pathway is known to be associated with cognitive impairments (Shu et al, 2013). Expression of PIP4K2A mRNA was also reported to be significantly increased in lymphocyte cell lines derived from schizophrenia patients (Saggers-Gray et al, 2011).…”

Acetyl-l-carnitine restores synaptic transmission and enhances the inducibility of stable LTP after oxygen–glucose deprivation

“…The PI3K/protein kinase B (Akt) pathway is important during the development of the central nervous system and plays a critical role in mediating survival signals in a wide range of circumstances (Brunet et al 2001). Furthermore, it has been well established that this signaling pathway mediates synaptic plasticity and memory (Horwood et al 2006), and is also involved in the cognitive impairment caused by chronic cerebral hypoperfusion (Shu et al 2013).…”