|Carey, Amanda - NORTHEASTERN UNIVERSITY|
|Brewer, Greg - SOUTHERN IL SCHOOL OF MED|
Submitted to: Journal of Alzheimer's Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 8, 2007
Publication Date: October 12, 2007
Citation: Joseph, J.A., Carey, A.N., Brewer, G.J., Lau, F.C., Fisher, D.R. 2007. Dopamine and ABeta-induced Stress Signaling and Decrements in CA2+ Buffering in Primary Neonatal Hippocampal Cells are Antagonized by Blueberry Extract. Journal of Alzheimer's Disease. 11:433-446. Interpretive Summary: We have previously shown that dietary blueberry extract supplement reversed several characteristics of brain and behavioral aging in rodents. Additionally, findings indicate that certain cells showed decrements in calcium dissipation following an action potential (a method of communication among brain cells, in which they release calcium that is eventually removed from the cell) that were counteracted by blueberry supplement. Since it has been postulated that at least part of the loss of intellectual function in aging may be dependent upon a dysregulation in calcium, we assessed whether a) calcium dissipation would be altered in brain cells that were exposed to dopamine or amyloid beta, which forms the plaques in the Alzheimer's brain and b) blueberry pre-treatment of the cells would prevents these deficits. Thus brain cells that were not treated with blueberry and cells that were treated with blueberry were exposed to dopamine and different forms of amyloid beta (amyloid beta(40), amyloid beta(42), amyloid beta(25-35)). Calcium dissipation following an induced action potential was assessed. Results indicated that dopamine significantly lowered calcium dissipation in the brain cells at all time points examined after the action potential. However, blueberry treatment selectively prevent these declines in calcium. In the case of amyloid beta, the greatest effects of calcium were seen when the cells were treated with amyloid beta(42). These effects were also counteracted by blueberry treatment. Amyloid beta(40) produced fewer deficits on calcium dissipation than those seen when the brain cells were pre-treated with either amyloid beta(40) or amyloid beta(25-35). Additional analyses indicated that blueberries may be exerting their protective effects in the brain cells by altering levels of communication molecules. Therefore, it appears that at least part of the protective effect of blueberries may involve alterations in the signaling of stress.
Technical Abstract: We have shown previously that dietary blueberry (BB) extract supplementation (S) reversed several parameters of neuronal and behavioral (e.g., cognition) aging in rodents. Additionally, findings indicate that COS-7 cells transfected with muscarinic receptor subtypes (e.g., M1) showed decrements in Ca2+ clearance following depolarization (Ca2+ Recovery time, Ca2+RT) that were antagonized by BB. Since it has been postulated that at least part of the loss of cognitive function in aging may be dependent upon a dysregulation in calcium homeostasis (i.e., Ca2+RT), we assessed whether: a) Ca2+RT would be altered in dopamine (DA)- or amyloid beta (A')-exposed cultured primary hippocampal neuronal cells (HNC), and b) BB pre-treatment of the cells would prevent these deficits. Thus, control or BB (0.5mg/ml)-treated HNC were exposed to DA (0.1mM, 2hrs), A'(40) (25'M, 24hrs), A'(42) (25'M, 24hrs), and A'(25-35) (25'M, 24hrs), and Ca2+RT following KCl-induced depolarization assessed. Ca2+RT was assessed as the % of HNC showing recovery to 50% -70% of control at 5, 10, or 15 min after depolarization. Results indicated that DA significantly lowered Ca2+RT in the HNC at all time points examined after depolarization. However, BB treatment selectively prevented these declines in Ca2+RT. In the case of A', the greatest effects on Ca2+RT were seen when the hippocampal cells were A'(42)-treated. These effects were antagonized by BB treatment. A'(40) produced fewer deficits on Ca2+RT than those seen when the HNC were pre-treated with either A'(42) or A'(25-35), but BB was relatively ineffective in antagonizing the deficits in Ca2+RT produced by A'(40) or A'(25-35). Additional analyses indicated that BBs may be exerting their protective effects in the hippocampal cells by altering levels of phosphorylated MAPK, PKC', and phosphorylated CREB. Therefore it appears that at least part of the protective effect of BBs may involve alterations in stress signaling.