Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation.
Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit microglial activation. In Alzheimer's disease brain, a number of proteins, including serum amyloid P component (SAP) and complement factors such as C1q, accumulate in amyloid beta (Abeta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in Abeta plaques. Furthermore, SAP and C1q enhanced Abeta fibril formation and Abeta mediated cytokine release by human microglia in vitro. In the present study, we report that tetracycline and minocycline dose-dependently reduce TNF-alpha and IL-6 release by adult human microglia upon stimulation with a combination of Abeta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of Abeta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with Abeta alone as well as with Abeta in combination with SAP and C1q. Our data suggest that minocycline and tetracycline at tolerable doses can inhibit human microglial activation. This activity in part is exerted by inhibition of (SAP and C1q enhanced) Abeta fibril formation.
Familian
Atoosa
A
Department of Psychiatry, Institute for Clinical and Experimental Neurosciences-VU (ICEN-VU), VU University Medical Center, Amsterdam, The Netherlands. a.familian@vumc.nl
Boshuizen
Ronald S
RS
Eikelenboom
Piet
P
Veerhuis
Robert
R
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D001921:Brain / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D008262:Macrophage Activation / Q000187:drug effects; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D009454:Neurofibrils / Q000187:drug effects*; D000683:Serum Amyloid P-Component / Q000378:metabolism; D013268:Stimulation, Chemical; D013752:Tetracycline / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D016207:Cytokines; D000683:Serum Amyloid P-Component; D013844:Thiazoles; C009462:thioflavin T; D015922:Complement C1q; D013752:Tetracycline; D008911:Minocycline