Abeta peptide conformation determines uptake and interleukin-1alpha expression by primary microglial cells.
Microglia clear amyloid beta (Abeta) after immunization. The interaction of Abeta with the microglial cell surface also results in cytokine expression. Soluble oligomers and protofibrils of Abeta may be more neurotoxic than Abeta fibrils. We investigated the effects of oligomeric, protofibrillar and fibrillar Abeta40 and Abeta42 peptides on uptake and IL-1alpha expression by primary microglia. Abeta peptide assemblies were extensively characterized. Primary microglial cells were exposed to different Abeta40 and Abeta42 assemblies and IL-1alpha expression was quantified. To study uptake, microglial cells were exposed to different assemblies of Cy3-labeled Abeta. We found that Abeta42 and Abeta40 oligomers and fibrils induced IL-1alpha expression, but protofibrils did not. We also observed that all forms of Abeta42 (oligomer, protofibril and fibril) and Abeta40 fibrils were taken up by the microglial cells. These results demonstrate that microglial cells can take up non-fibrillar Abeta and that oligomeric peptide induces an inflammatory response. The uptake of oligomeric and protofibrillar Abeta by microglia merits further investigation as a potential means for removing these neurotoxic species from the brain.
Parvathy
Saravanapavan
S
Neuroscience Research Laboratories, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5485, United States.
Rajadas
Jayakumar
J
Ryan
Heather
H
Vaziri
Sepideh
S
Anderson
Laurel
L
Murphy
Greer M
GM
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D052160:Benzothiazoles; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D053582:Interleukin-1alpha / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D016207:Cytokines; D053582:Interleukin-1alpha; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D007770:L-Lactate Dehydrogenase