Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostaglandin E2 release in primary midbrain astrocytes.
Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid beta peptide 25-35 (Abeta(25-35)) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E(2) (PGE(2)) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Abeta(25-35)-induced COX-2/PGE(2) synthesis. PKC-inhibitors prevent Abeta(25-35)-induced COX-2 and PGE(2) synthesis. Furthermore Abeta(25-35) rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms alpha and/or beta are most probably involved in Abeta(25-35)-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition.
Hüll
Michael
M
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany. michael_huell@psyallg.ukl.uni-freiburg.de
Müksch
Barbara
B
Akundi
Ravi Shankar
RS
Waschbisch
Anne
A
Hoozemans
Jeroen J M
JJ
Veerhuis
Robert
R
Fiebich
Bernd L
BL
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D015232:Dinoprostone