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Published on: July 15, 2010
Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation
Atoosa Familian1, Ronald S Boshuizen, Piet Eikelenboom
1Department of Psychiatry, Institute for Clinical and Experimental Neurosciences-VU (ICEN-VU), VU University Medical Center, Amsterdam, The Netherlands. a.familian@vumc.nl
Abstract:
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.
Insights
Minocycline and tetracycline reduce inflammatory responses in human microglia by inhibiting amyloid-beta plaque formation. These findings suggest potential therapeutic benefits for neurodegenerative diseases like Alzheimer's.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Minocycline, a tetracycline derivative, shows neuroprotection and is used in clinical trials for neurodegenerative diseases.
- Minocycline crosses the blood-brain barrier and is thought to inhibit microglial activation.
- Alzheimer's disease brains feature amyloid-beta (Abeta) plaques with accumulated proteins like serum amyloid P component (SAP) and C1q.
Purpose of the Study:
- To investigate the effects of minocycline and tetracycline on human microglial activation.
- To determine if these antibiotics inhibit Abeta fibril formation.
- To explore the potential of minocycline and tetracycline as treatments for neuroinflammation.
Main Methods:
- Adult human microglia were stimulated with Abeta, SAP, and C1q.
- Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release were measured.
- Abeta fibril formation was assessed using a thioflavin-S fluorescence test.
Main Results:
- Minocycline and tetracycline dose-dependently reduced TNF-alpha and IL-6 release from human microglia.
- Both antibiotics inhibited Abeta fibril formation, with minocycline showing a stronger effect.
- Inhibition of fibril formation occurred with Abeta alone and in combination with SAP and C1q.
Conclusions:
- Minocycline and tetracycline can inhibit human microglial activation at tolerable doses.
- These effects are partly mediated by the inhibition of Abeta fibril formation, including SAP and C1q enhanced formation.
- The findings support the potential of minocycline and tetracycline in managing neuroinflammation associated with neurodegenerative diseases.
