ABSTRACT
Title
Soluble beta amyloid and its effect on HPA axis function
Authors
MG. Morgese1, S. Schiavone1,2, L. Trabace1 and V. Cuomo3
1Dept. of Biomedical Sciences, School of Medicine, University of Foggia, Italy
2 Dept. of Pathology and Immunology, University of Geneva, Switzerland
3 Dept. of Human Physiology and Pharmacology Vittorio Erspamer, University of Rome, La Sapienza, Italy
1Dept. of Biomedical Sciences, School of Medicine, University of Foggia, Italy
2 Dept. of Pathology and Immunology, University of Geneva, Switzerland
3 Dept. of Human Physiology and Pharmacology Vittorio Erspamer, University of Rome, La Sapienza, Italy
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis plays a critic role in the stress response. An impaired HPA axis function in depression has been widely documented (Kunugi et al, 2006). On the other hand, alterations in cortisol levels have been reported in Alzheimer’s disease (AD) patients (Bao et al, 2008). Moreover, depression is common in pre-clinical AD, and may represent an early manifestation of the disease before appearing any cognitive impairment (Visser et al, 2000).
We have previously demonstrated that soluble beta amyloid (BA), the major senile plaque component in AD, is able to provoke depressive-like profile as evidenced by the forced swimming test (FST), together with prefrontal cortex (PFC) alterations in the expression of BDNF and serotonergic transmission (Colaianna et al, 2010). To further evaluate the behavioural data, we performed the sucrose preference test (SPT). Interestingly, this behavioural paradigm was not affected by the soluble peptide 7 days after administration. Instead of SPT, FST is characterised by a stressful condition of behavioural despair; therefore, the different results obtained from these tests leads us to hypothesize a different response to stress coping behaviour. Consistent with this hypothesis, we investigated the effects of BA on two different cognitive behavioural paradigms, such as the passive avoidance test (PAT) and the novel object recognition test (NORT), associated and not with stressor stimuli, respectively. In line with emotional and behavioural data, we found that soluble AB was not able to induce any impairment in the parameters studied in NORT (exploratory activity novel vs familiar, two way ANOVA, F(1,46)=33.64, P<0.001; discrimination index, one way ANOVA, F(2,23)=0.44, n.s.); however, in the passive avoidance task, BA-treated animals showed an impaired memory consolidation of inhibitory avoidance training (retention time, one way ANOVA, F(2,23) = 0.43; n.s.).
In order to correlate behavioural with neurochemical data, we investigated the effects of the peptide on noradrenergic system in amygdala (AMY), PFC and hippocampus (HIPP), areas known to process stress-related information (Mello et al, 2003). Indeed, these areas control HPA exhibiting a positive (AMY) (Anda et al, 2007) or negative control (PFC and HIPP) (Harvey et al, 2006). We found that soluble BA caused a significant increase in NA in PFC and HIPP seven days after peptide injection (unpaired t-test, P<0.05), while in AMY, BA was able to decrease NA (unpaired t-test, P<0.05), indicating an inhibitory effect on HPA axis activation. Consistently, we found a significant decrease in plasma corticosterone concentrations (unpaired t-test, P<0.05) in BA-treated rats.
In conclusion, our data suggest that BA alters HPA axis function modulating noradrenergic neurotransmission in cerebral areas involved in stress response.
Kunugi et al. (2006). Neuropsychopharmacology. 31, 212–220.
Bao et al. (2008). Brain Res Rev. 57, 531-553.
Visser et al. (2000). J Am Geriatr Soc. 48, 479-484.
Colaianna et al. (2010). Br J Pharmacol. 159, 1704-1715.
Mello et al. (2003). Rev Bras Psiquiatr. 25, 231-8.
Anda et al. (2007). Neurobiol Learn Mem. 87, 57–66.
Harvey et al. (2006). Physiol Behav. 87, 881–890.
We have previously demonstrated that soluble beta amyloid (BA), the major senile plaque component in AD, is able to provoke depressive-like profile as evidenced by the forced swimming test (FST), together with prefrontal cortex (PFC) alterations in the expression of BDNF and serotonergic transmission (Colaianna et al, 2010). To further evaluate the behavioural data, we performed the sucrose preference test (SPT). Interestingly, this behavioural paradigm was not affected by the soluble peptide 7 days after administration. Instead of SPT, FST is characterised by a stressful condition of behavioural despair; therefore, the different results obtained from these tests leads us to hypothesize a different response to stress coping behaviour. Consistent with this hypothesis, we investigated the effects of BA on two different cognitive behavioural paradigms, such as the passive avoidance test (PAT) and the novel object recognition test (NORT), associated and not with stressor stimuli, respectively. In line with emotional and behavioural data, we found that soluble AB was not able to induce any impairment in the parameters studied in NORT (exploratory activity novel vs familiar, two way ANOVA, F(1,46)=33.64, P<0.001; discrimination index, one way ANOVA, F(2,23)=0.44, n.s.); however, in the passive avoidance task, BA-treated animals showed an impaired memory consolidation of inhibitory avoidance training (retention time, one way ANOVA, F(2,23) = 0.43; n.s.).
In order to correlate behavioural with neurochemical data, we investigated the effects of the peptide on noradrenergic system in amygdala (AMY), PFC and hippocampus (HIPP), areas known to process stress-related information (Mello et al, 2003). Indeed, these areas control HPA exhibiting a positive (AMY) (Anda et al, 2007) or negative control (PFC and HIPP) (Harvey et al, 2006). We found that soluble BA caused a significant increase in NA in PFC and HIPP seven days after peptide injection (unpaired t-test, P<0.05), while in AMY, BA was able to decrease NA (unpaired t-test, P<0.05), indicating an inhibitory effect on HPA axis activation. Consistently, we found a significant decrease in plasma corticosterone concentrations (unpaired t-test, P<0.05) in BA-treated rats.
In conclusion, our data suggest that BA alters HPA axis function modulating noradrenergic neurotransmission in cerebral areas involved in stress response.
Kunugi et al. (2006). Neuropsychopharmacology. 31, 212–220.
Bao et al. (2008). Brain Res Rev. 57, 531-553.
Visser et al. (2000). J Am Geriatr Soc. 48, 479-484.
Colaianna et al. (2010). Br J Pharmacol. 159, 1704-1715.
Mello et al. (2003). Rev Bras Psiquiatr. 25, 231-8.
Anda et al. (2007). Neurobiol Learn Mem. 87, 57–66.
Harvey et al. (2006). Physiol Behav. 87, 881–890.