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.
Highlights
Alzheimer’s disease and vascular dementia are the most common causes of cognitive impairment in the elderly
The total exploring time increased in the 2-VO 4 weeks group and the 2VO 8 weeks group when compared with the 2-VO 1 week group (P,0.01), but there was no difference between the 2-VO 4 weeks group and the 2-VO 8 weeks group (P.0.05, see Figure 1A)
To determine whether the group differences in escape latency were due to differences in swimming ability, the swim speed was calculated for each group.We found that the 2-VO procedure did affect swimming rate [F (3, 20) = 0.2097, P = 0.8885; Figure 2C]
Summary
Alzheimer’s disease and vascular dementia are the most common causes of cognitive impairment in the elderly. A number of clinical studies have identified cerebral hypoperfusion in brain regions associated with the cognitive functions both in Alzheimer’s disease and vascular dementia patients[1,2,3]. Using the 2-VO model, our previous studies found that after 2-VO treatment, the learning capacity and memory of the subjects are gradually impaired and 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, phosphorylated cyclic AMP-responsive element binding protein and tau hyperphosphorylation are altered within the hippocampus. The underlying mechanisms connecting CCH-induced protein expression and the observed behavioral impairment remains largely unknown
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