Dopamine and Abeta-induced stress signaling and decrements in Ca2+ buffering in primary neonatal hippocampal cells are antagonized by blueberry extract

J Alzheimers Dis. 2007 Jul;11(4):433-46. doi: 10.3233/jad-2007-11404.


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 Ca;{2+} clearance following depolarization (Ca;{2+} Recovery time, Ca;{2+}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., Ca;{2+}RT), we assessed whether: a) Ca;{2+}RT would be altered in dopamine (DA)- or amyloid beta (Abeta)-exposed cultured primary hippocampal neuronal cells (HNC), and b) BB pre-treatment of the cells would prevent these deficits. Thus, control or BB (0.5 mg/ml)-treated HNC were exposed to DA (0.1 mM, 2 hrs), Abeta(40) (25 microM, 24 hrs), Abeta(42) (25 microM, 24 hrs), and Abeta(25-35) (25 microM, 24 hrs), and Ca;{2+}RT following KCl-induced depolarization assessed. Ca;{2+}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 Ca;{2+}RT in the HNC at all time points examined after depolarization. However, BB treatment selectively prevented these declines in Ca;{2+}RT. In the case of Abeta, the greatest effects on Ca;{2+}RT were seen when the hippocampal cells were Abeta(42)-treated. These effects were antagonized by BB treatment. Abeta(40) produced fewer deficits on Ca;{2+}RT than those seen when the HNC were pre-treated with either A;{2+}(42) or A;{2+}(25-35), but BB was relatively ineffective in antagonizing the deficits in Ca;{2+}RT produced by A;{2+}(40) or A;{2+}(25-35). Additional analyses indicated that BBs may be exerting their protective effects in the hippocampal cells by altering levels of phosphorylated MAPK, PKCgamma, and phosphorylated CREB. Therefore it appears that at least part of the protective effect of BBs may involve alterations in stress signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Peptides / physiology*
  • Animals
  • Antioxidants / pharmacology*
  • Blueberry Plants*
  • Calcium / metabolism*
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dopamine / physiology*
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • Homeostasis / drug effects*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase Kinases
  • Neurons / drug effects
  • Neurons / physiology
  • Oxidative Stress / drug effects*
  • Phytotherapy*
  • Plant Extracts / pharmacology*
  • Protein Kinase C / metabolism
  • Rats
  • Receptors, Muscarinic / drug effects
  • Signal Transduction / drug effects*


  • Amyloid beta-Peptides
  • Antioxidants
  • Cyclic AMP Response Element-Binding Protein
  • Plant Extracts
  • Receptors, Muscarinic
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase Kinases
  • Calcium
  • Dopamine