Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease.
Bone marrow (BM)-derived monocytes contribute to the development of microglial reaction around beta-amyloid (Abeta) plaques in Alzheimer's disease (AD) and possibly clear Abeta. Therefore, it is of great importance to separate the proinflammatory actions of monocytic cells from Abeta phagocytic effects. We used minocycline (mino) to systemically downregulate microglial activation and studied proliferation, expression of markers for activated microglia, and Abeta removal in vitro and in vivo. Mino did not affect proliferation or phagocytic activity of BM-derived cells toward Abeta in vitro. Intrahippocampal LPS injection used to induce inflammation and increase recruitment of BM cells from periphery, reduced Abeta burden in BM-transplanted AD transgenic mice. All engrafted cells expressed CD45, approximately 50% expressed Iba-1, and <0.5% of these cells expressed CD3e. About 40% of the engrafted cells were mitotically active. LPS increased immunoreactivity for Iba-1, MHC II, a marker of antigen presenting cells, and CD68, a marker of lysosomal activity. The endogenous microglia largely contributed to these LPS-induced immunoreactivities. Mino reduced the engraftment of BM-derived cells and blocked the LPS-induced MHC II and Iba-1 immunoreactivities, but did not prevent the increased CD68-immunoreactivity or the reduced Abeta burden. Importantly, mino did not block the association of eGFP-positive cells with Abeta deposits and the percentage of mitotically active BM-derived cells. In conclusion, mino reduces overall inflammatory potential of BM-derived monocytic cells without preventing their phagocytic activity. The separation of harmful activation of microglia/monocytic cells from their Abeta clearing mechanism may hold important therapeutic potential.
Malm
Tarja M
TM
Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio, FI-70211, Kuopio, Finland.
Magga
Johanna
J
Kuh
Georges Ful
GF
Vatanen
Tero
T
Koistinaho
Milla
M
Koistinaho
Jari
J
D000544:Alzheimer Disease / Q000503:physiopathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D008911:Minocycline