Perturbations in calcium-mediated signal transduction in microglia from Alzheimer's disease patients.
Calcium-sensitive fluorescence microscopy has been used to study Ca2+-dependent signal transduction pathways in microglia obtained from Alzheimer's disease (AD) patients and non-demented (ND) individuals. Data were obtained from nine AD cases and seven ND individuals and included basal levels of intracellular Ca2+ [Ca2+]i, peak amplitudes (Delta[Ca2+]i) and time courses of adenosine triphosphate (ATP) responses and amplitudes of an initial transient response and a subsequent second component of Ca2+ influx through store-operated channels (SOC) induced by platelet-activating factor (PAF). Overall, AD microglia were characterized by significantly higher (20%) basal Ca2+ [Ca2+]i relative to ND cells. The Delta[Ca2+]i of ATP and initial phase of PAF responses, which reflect rapid depletion of Ca2+ from endoplasmic reticulum stores, were reduced by respective values of 63% and 59% in AD cells relative to amplitudes recorded from ND microglia. Additionally, AD microglia showed diminished amplitudes (reduction of 61%) of SOC-mediated Ca2+ entry induced by PAF and prolonged time courses (increase of 60%) of ATP responses with respect to ND microglia. We have generally replicated these results with exposure of human fetal microglia to beta amyloid (5 microM Abeta1-42 applied for 24 hr). Overall, these data indicate significant abnormalities are present in Ca2+-mediated signal transduction in microglia isolated from AD patients.
McLarnon
James G
JG
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. mclarnon@interchange.ubc.ca
Choi
Hyun B
HB
Lue
Lih-Fen
LF
Walker
Douglas G
DG
Kim
Seung U
SU
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000704:Analysis of Variance; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D005333:Fetus; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011180:Postmortem Changes; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013050:Spectrometry, Fluorescence / Q000379:methods
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010972:Platelet Activating Factor; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D002118:Calcium