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Title: Blueberry antagonism of C-2 ceramide disruption of Ca2+ responses and recovery in MAChR-transfected COS-7 cells involves alterations in stress signaling

Author
item Joseph, James
item BIELINSKI, DONNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Fisher, Derek

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2010
Publication Date: 3/24/2010
Citation: Joseph, J.A., Bielinski, D., Fisher, D.R. 2010. Blueberry antagonism of C-2 ceramide disruption of Ca2+ responses and recovery in MAChR-transfected COS-7 cells involves alterations in stress signaling. Journal of Agricultural Food & Chemistry. 58:3380-3392.

Interpretive Summary: A specific brain cells (muscarinic receptors, MR) that are selectively sensitive to oxidative stress (OS) show loss of function in aging and Alzheimer disease. However, pretreatment of certain type of cells by blueberry (BB) extracts appear to prevent these deficits. In this study, we investigated the effects of BB on the interactions between MR and another type of brain cells (Cer) that are capable to produce C2 ceramide, a lipid exhibiting age-related negative cellular effects. We found that BB treatment can significantly antagonize the negative impacts of Cer. Possible origins on the effects of BB treatment were also explored. The obtained information is valuable for considering the use of BB to treat aging or Alzheimer’s disease induced loss of brain functions.

Technical Abstract: Muscarinic receptors (MAChRs) show loss of sensitivity in aging and AD, and are selectively sensitive to oxidative stress sensitivity (OSS), transfected (tn) with MAChR subtype M1 showing > OSS [the ability of the cell to extrude or sequester Ca2+ following depolarization (Recovery) by oxotremorine (oxo) and exposure to DA or amyloid beta42, ABeta42] than M3 tn COS-7 cells. Blueberry (BB) extract pretreatment prevented these deficits. Previous research has suggested that that C2 ceramide (Cer) has several age-related negative cellular effects (e.g., OS). When these cells were treated with Cer, the significant decrements in the ability of both types of tn cells to initially respond (Response) to oxo were antagonized by BB treatment. Present experiments assessed signaling mechanisms involved in the BB protection by exposing control or BB-treated M1 or M3 tn COS-7 cells to DA or ABETA42 in the presence or absence of Cer. Primarily, results showed that the effects of DA or ABETA42 were to increase stress (e.g., PKC', p38MAPK) and protective signals (e.g., pMAPK). Cer also appeared to raise several of the stress and protective signals in the absence of the other stressors, including PKCgamma, pJNK, pNfkappaB, p53, and p38MAPK, while not significantly altering MAPK, or Akt. pArc was, however, increased by ceramide in both types of transfected cells. The protective effects of BB when combined with ceramide generally showed greater protection when BB extract was applied prior to ceramide, except for one protective signal (pArc) where a greater effect was seen in the M3 cells exposed to ABETA42. In the absence of the ABETA42 or DA, BB, for several of the stress signals (e.g., pNfkappaB, p53), lowered their ceramide-induced increases in M1- and M3-transfected cells. We are exploring these interactions further, but it is clear that increases in ceramide, to the same levels as are seen in aging, can have profound effects on calcium clearance and signaling during oxidative stress.