Inhibitory effect of minocycline on amyloid β 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 (A beta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in A beta plaques. Furthermore, SAP and C1q enhanced A beta fibril formation and A beta 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 A beta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of A beta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with A beta alone as well as with A beta 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) A beta fibril formation. (C) 2005 Wiley-Liss, Inc.