Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice.
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.
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. tseabrook@rics.bwh.harvard.edu
Timothy J
TJ
Seabrook
Liying
L
Jiang
Marcel
M
Maier
Cynthia A
CA
Lemere
D000367:Age Factors; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000009:adverse effects; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008911:Minocycline