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Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M. 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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Emory University
The protean and itinerant nature of phagocytes has compelled researchers to devise increasingly ingenious experiments to establish their role in brain disorders, as exemplified nicely by the studies of Mildner et al. and Ajami et al. These researchers make a reasonably compelling case that significant infiltration of the brain by peripheral, bone marrow-derived macrophages requires a weakening of normal host barriers. Since phagocytes exist on both sides of the cerebrovascular wall, does it matter to the brain where the cells come from? I think it does; there is growing evidence for functional specialization in otherwise similar-appearing macrophages, and (from an evolutionary perspective) why would the brain be endowed with such an effective—and selective—obstacle to circulating phagocytes if their pedigree was unimportant?
Regarding the enduring discussion of the role of phagocytes in Alzheimer disease, one additional issue—cerebral β amyloid angiopathy (CAA)—is worth a comment. The degree of CAA in Alzheimer disease is highly variable, but affected vessels can be appreciably impaired, as evidenced by an elevated risk of hemorrhagic stroke. It is therefore conceivable that CAA might augment the infiltration of circulating monocytes into the brain, thereby modifying the pathologic signature and course of disease. On the flip side, the presence of CAA could reflect subtle functional differences in brain phagocytes. El Khoury et al., 2007 found that the disruption of microglial accumulation via Ccr2 deficiency causes the early appearance of CAA and microhemorrhage in APP-transgenic mice. Phagocytes thus may help to regulate the compartmentalization of Aβ aggregates in brain, suggesting that the presence and phenotype of these cells can influence the risk of CAA in older humans.
References:
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.
View all comments by Lary WalkerHarvard Medical School
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:
Dickstein DL, Biron KE, Ujiie M, Pfeifer CG, Jeffries AR, Jefferies WA. Abeta peptide immunization restores blood-brain barrier integrity in Alzheimer disease. FASEB J. 2006 Mar;20(3):426-33. PubMed.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. 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.
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.
Fiala M, Zhang L, Gan X, Sherry B, Taub D, Graves MC, Hama S, Way D, Weinand M, Witte M, Lorton D, Kuo YM, Roher AE. Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model. Mol Med. 1998 Jul;4(7):480-9. PubMed.
Giri R, Shen Y, Stins M, Du Yan S, Schmidt AM, Stern D, Kim KS, Zlokovic B, Kalra VK. 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.
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.
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