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 β‐amyloid (Aβ) plaques in Alzheimer's disease (AD) and possibly clear Aβ. Therefore, it is of great importance to separate the proinflammatory actions of monocytic cells from Aβ phagocytic effects. We used minocycline (mino) to systemically downregulate microglial activation and studied proliferation, expression of markers for activated microglia, and Aβ removal in vitro and in vivo . Mino did not affect proliferation or phagocytic activity of BM‐derived cells toward Aβ in vitro . Intrahippocampal LPS injection used to induce inflammation and increase recruitment of BM cells from periphery, reduced Aβ burden in BM‐transplanted AD transgenic mice. All engrafted cells expressed CD45, ∼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 Aβ burden. Importantly, mino did not block the association of eGFP‐positive cells with Aβ 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 Aβ clearing mechanism may hold important therapeutic potential. © 2008 Wiley‐Liss, Inc.