Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus.
The expression of the purinergic receptor subtype P2X(7)R, a nonselective cationic channel activated by high levels of adenosine triphosphate (ATP), has been studied in adult microglia obtained from Alzheimer disease (AD) and nondemented (ND) brains, in fetal human microglia exposed to Abeta(1-42) peptide and in vivo in Abeta(1-42)-injected rat hippocampus. Semiquantitative reverse transcriptase-polymerase chain reaction showed enhanced expression (increase of 70%) of P2X(7)R in AD microglia compared with ND cells (analysis of 6 AD and 8 ND cases). Immunohistochemical analysis showed prominent P2X(7)R expression in association with Abeta plaques and localized to HLA-DR-immunoreactive microglia. In cultured fetal human microglia, cells exposed to Abeta(1-42) (5 microM for 18 hours) had significantly elevated levels of P2X(7)R (by 106%) compared with untreated cells. Amplitudes of Ca(2+) responses in these cells, induced by the selective P2X(7)R agonist BzATP, were increased by 145% with Abeta(1-42) pretreatment relative to control (no peptide pretreatment) and were largely blocked if the P2X(7)R inhibitor-oxidized ATP (oxATP) was added with peptide in pretreatment solution. In vivo, double immunostaining analysis showed considerable P2X(7)R colocalized with microglia after injection of Abeta(1-42) (1 nmol) into rat hippocampus. The overall results suggest roles of P2X(7)R in mediating microglial purinergic inflammatory responses in AD brain.
McLarnon
James G
JG
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver BC, Canada. mclarnon@interchange.ubc.ca
Ryu
Jae K
JK
Walker
Douglas G
DG
Choi
Hyun B
HB
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000345:Affinity Labels / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000378:metabolism; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis*; D058486:Receptors, Purinergic P2X7; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000345:Affinity Labels; D016229:Amyloid beta-Peptides; D006684:HLA-DR Antigens; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D010455:Peptides; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D002118:Calcium