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Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice
Timothy J Seabrook1, Liying Jiang, Marcel Maier
1Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. tseabrook@rics.bwh.harvard.edu
Abstract:
Activated microglia and reactive astrocytes invade and surround cerebral beta amyloid (Abeta) plaques in Alzheimer's disease (AD), but the role of microglia in plaque development is still unclear. In this study, minocycline was administered for 3 months, prior to and early in Abeta plaque formation in amyloid precursor protein transgenic mice (APP-tg). When minocycline was given to younger mice, there was a small but significant increase in Abeta deposition in the hippocampus, concurrent with improved cognitive performance relative to vehicle treated mice. If APP-tg mice received minocycline after Abeta deposition had begun, microglial activation was suppressed but this did not affect Abeta deposition or improve cognitive performance. In vitro studies demonstrated that minocycline suppressed microglial production of IL-1beta, IL-6, TNF, and NGF. Thus, minocycline has different effects on Abeta plaque deposition and microglia activation depending on the age of administration. Our data suggest that this may be due to the effects of minocycline on microglial function. Therefore, anti-inflammatory therapies to suppress microglial activation or function may reduce cytokine production but enhance Abeta plaque formation early in AD.
Insights
Minocycline given early to Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia and astrocytes surround amyloid plaques in Alzheimer's disease (AD).
- The role of microglia in plaque development remains unclear.
- Minocycline is an antibiotic with anti-inflammatory properties.
Purpose of the Study:
- To investigate the effect of minocycline on amyloid-beta (Abeta) plaque deposition and cognitive function in a mouse model of AD.
- To determine if the timing of minocycline administration influences its effects on Abeta plaques and microglia activation.
Main Methods:
- Amyloid precursor protein transgenic mice (APP-tg) were treated with minocycline for 3 months.
- Minocycline was administered either before plaque formation or after deposition had begun.
- Cognitive performance and Abeta deposition were assessed.
- In vitro studies examined minocycline's effect on microglial cytokine production.
Main Results:
- Early minocycline administration in young APP-tg mice led to increased Abeta deposition and improved cognitive performance.
- Late minocycline administration suppressed microglial activation but did not alter Abeta deposition or cognitive function.
- In vitro, minocycline suppressed microglial production of IL-1beta, IL-6, TNF, and NGF.
Conclusions:
- Minocycline's effects on Abeta deposition and microglial activation depend on the timing of administration.
- Early intervention may enhance Abeta plaque formation despite reducing inflammation.
- Anti-inflammatory therapies targeting microglia may have complex effects on AD pathogenesis.
