. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007 Dec;10(12):1544-53. PubMed.

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  1. This is a very interesting paper. It presents compelling evidence that when the blood-brain barrier is damaged, Ly-6hiCcr2+ monocytes are direct circulating precursors of microglia in the blood. This is the most convincing evidence so far that a specific subset of circulating monocytes can develop into microglia.

    The implications for Alzheimer disease remain to be seen. Our own recent data clearly shows that in APP transgenic mice, early microglial accumulation in the brain is Ccr2 dependent, and several of these cells have surface characteristics of blood monocytes. The blood-brain barrier in AD mouse models (and likely in AD) is far from intact functionally (Dickstein et al., 2006) as it allows the influx of antibodies (Bard et al., 2000) and of circulating Aβ from the blood into the brain (Deane et al., 2003). In addition, in-vitro data using a model for the BBB indicate that interaction of Aβ42 with monocytes or endothelial cells on the brain side potentiated monocyte transmigration from the blood side to the brain side (Fiala et al., 1998; Giri et al., 2000). A possible scenario is that in AD, the “damaged” or activated BBB cells (perhaps as a result of Aβ deposition) facilitate the passage of Ly-6hiCCR2+ monocytes from the blood into the brain and the subsequent accumulation of these cells, which will ultimately differentiate into microglia. In support of this scenario, we found that in the absence of Ccr2, the initial site for Aβ accumulation is around blood vessels (El Khoury et al., 2007).

    I believe these findings illustrate that much work is further needed to fully understand the role of microglia in AD and how they accumulate in the brain in response to amyloid deposition.

    References:

    . Abeta peptide immunization restores blood-brain barrier integrity in Alzheimer disease. FASEB J. 2006 Mar;20(3):426-33. PubMed.

    . Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000 Aug;6(8):916-9. PubMed.

    . RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.

    . Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model. Mol Med. 1998 Jul;4(7):480-9. PubMed.

    . beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol. 2000 Dec;279(6):C1772-81. PubMed.

    . Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.