. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008 Aug 13;28(33):8354-60. PubMed.

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  1. I’d like to make two major points about this paper from Hickman and colleagues.

    First, I don’t view changing gene expression in microglia as a dysfunction. Microglia change their protein synthesis all the time, including surface receptors and proinflammatory cytokines, especially when activated under conditions of acute injury. The changes reported here for PS1-APP mice seem to be a result of the genetic manipulations in these mice since they do not occur in wild-type cells.

    Second, the role of microglia in amyloid clearance remains controversial. Certainly, the histopathology of human brain does not support a role for microglia in amyloid clearance, especially when it comes to early diffuse amyloid, which does not seem to elicit any kind of response from microglia, i.e., the cells remain in their resting state.

    That said, I do feel that understanding the role of microglia in AD is key to devising new treatments. I also think that microglial dysfunction plays a role, but in the sense that microglia themselves are subject to degeneration, resulting in a dysfunction that manifests itself in a loss of neuroprotection. In other words, I think that neurodegeneration in AD results from neglect (due to a loss of microglia) rather than from aggression (due to neuroinflammation).

    View all comments by Wolfgang Streit
  2. The timely report by Hickman, Allison, and El Khoury presents an interesting interpretation of the interplay between microglia and cerebral amyloidosis. It has long been established that Tg2576 mice manifest microglial activation concomitant with Abeta deposition, and that before plaques develop these animals have very little microgliosis (see for example Benzing et al., 1999). These authors have performed a related study in the APPPS1 mice developed by Joanna Jankowsky and David Borchelt (Jankowsky et al., 2001) and find a similar phenomenon.

    They open their abstract by stating that “Early microglial accumulation in Alzheimer’s disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques”. However, I'd like to note that this is a controversial statement, for which the authors do not present experimental evidence. Early ultrastructural studies from Henryk Wisniewski and Jerzy Wegiel actually suggested the opposite, that early microglial activation is a key factor in promoting progression of cerebral amyloidosis (Wisniewski and Wegiel, 1994). Further, observations in Tg2576 mice do not support an association between reactive microglia and diffuse beta-amyloid deposits (only between activated microglia and mature Abeta deposits, Benzing et al., 1999). This seems partially at odds with the authors’ contention.

    Certainly, there are at least two interpretations for the observation of microglial activation occurring in tight temporal and spatial association with more mature beta-amyloid plaques. 1) That, as the authors contend, reactive microglia begin to clear non-deposited (i.e., soluble oligomeric) forms of Abeta and then become easily overwhelmed, or 2) that the microglia become activated in response to “seeds” (e.g., protofibrils or fibrils) of beta-amyloid plaques and then, via chronic, low-level production of pro-inflammatory cytokines and acute-phase reactants, contribute to plaque maturation. Probably the most direct support for the latter interpretation comes from the NSAID epidemiologic literature, where use of NSAIDs is associated with reduced microglial activation in humans (Mackenzie and Munoz, 1998) and as much as 50 percent reduced risk for AD (in t’Veld et al., 2001; Szekely et al., 2004). More recently at ICAD 2008, John Breitner showed impressively that naproxen given during the randomized controlled ADAPT trial for approximately 2 years duration and followed-up for another ~2 years results in reduced incidence of AD.

    But the real “meat” of the work by Hickman et al. comes from their FACS approach as applied to single brain cell suspensions from APPPS1 mice of different ages. Using this approach, the authors show that CD11b+ (presumed microglial) cells from younger APPPS1 animals (from 1.5 to 3 months old, before obvious manifestation of beta-amyloid plaques) appear remarkably similar to age-matched wild-type controls when measuring mRNA for the microglial Abeta uptake receptors SRA, CD36, and RAGE. Similar results where observed on the Abeta-degrading enzymes Insulysin, Neprilysin, and MMP9.

    However, a different pattern of results emerged when considering older (from 8 to 14 months) animals; in this case, APPPS1 mice had significant reductions in both the Abeta phagocytosis receptors and the Abeta degrading enzymes. Interestingly, these same older APPPS1 mice demonstrated up-regulation of mRNA for the pro-inflammatory cytokines IL-1beta and TNF-alpha, suggesting that these microglia are undergoing a phenotype “shift” from Abeta phagocytic, non-inflammatory to Abeta anti-phagocytic, pro-inflammatory.

    We have suggested something similar when we defined microglial activation as a continuum of responses ranging from productive (pro-phagocytic and anti-inflammatory) to deleterious (anti-phagocytic and pro-inflammatory) (Town et al., 2005). We agree with the authors that, to ensure productive clearance of Abeta by phagocytes such as microglia, therapies should promote an anti-inflammatory, pro-phagocytic phenotype. As in-vitro proof-of-concept, the authors show that treatment of N9 microglia with TNF-alpha reduces expression of SRA and CD36 and opposes Abeta uptake by these cells. We have observed something very similar when blocking the pro-inflammatory CD40-CD40L interaction on microglia – we then see increased Abeta uptake and clearance by microglia and reduced pro-inflammatory antigen presenting cell function (Tan, Town et al., 1999; Townsend, Town et al., 2005).

    One further issue that deserves mentioning is the origin of the CD11b+ cells that the authors have nicely characterized. It has now been clearly demonstrated that peripheral macrophages do enter brains of AD mice (Stalder et al., 2005; Simard et al., 2006; El Khoury et al., 2007), and most recently we have shown that boosting their brain entry by blocking TGF-betaRII signaling on these cells reduces AD-like pathology (Town et al., 2008). One wonders what percentage of the CD11b+ cells described by the authors are from the periphery. Nancy Ruddle has routinely used CD45int (brain-resident microglia) versus CD45hi (blood-borne macrophages) FACS staining to discriminate between the two populations (Juedes and Ruddle, 2001), and we have recently employed her protocol for this purpose (Town et al., 2008). The key question remains of whether these blood-borne macrophages are more efficient Abeta phagocytes than their long-term CNS-resident microglial cousins.

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    View all comments by Terrence Town