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  1. The study by Chan et al. follows nicely from previous work of the same group focused on the dissection of the molecular mechanisms underlying the genetic loci associated with AD risk.

    These studies are essential because the majority of the genetic variants associated with AD risk in genome-wide association studies are located in intergenic or intronic regions and it has not been straightforward to understand how these loci are functionally related to the disease. One assumption was that many of these variants would be associated with differences in gene expression. Failure to validate this premise for many of the loci indicated the need for studies such as this one, which performs protein quantitative trait analysis in a subset of cells expected to be important, or to mimic cells with known involvement in the pathological process of the disease. 

    This evaluation of the relation between known AD risk loci showed that the NME8 risk allele influences PTK2B, the CD33 risk allele influences TREM2, and the TREM1 risk allele is associated with a decreased TREM1/TREM2 ratio. The role of TREM2 in AD is still unclear and results from studies like this one are essential to better understand how genetic variability at this locus contributes to disease. In this case the results obtained favor a pathogenic role of increased TREM2 expression in myeloid cells from the periphery. 


    View all comments by Rita Guerreiro
  2. This article by Chan and colleagues offers new insights into the genetics and pathogenic effects of CD33 and TREM2 in Alzheimer’s disease (AD). CD33 was first implicated in AD in 2008, when we reported that the minor allele (G) of the rs3826656 single nucleotide polymorphism (SNP) in the CD33 gene confers risk for late-onset AD (Bertram et al., 2008). CD33 is a sialic acid-binding protein that we recently found to be expressed by microglial cells in the human aging brain (Griciuc et al., 2013). We had previously reported in vivo and in vitro evidence that CD33 inhibits microglia-mediated clearance of Aβ and promotes the formation of amyloid plaques in the brain (Griciuc et al., 2013). In the same study, we showed that the minor allele (A) of another CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression levels in microglial cells and insoluble Aβ42 levels in AD brain (Griciuc et al., 2013). In another study, the major allele (C) of rs3865444 was associated with increased CD33 expression levels in peripheral monocytes (Bradshaw et al., 2013). The molecular mechanisms underlying the effects of the rs3865444 and rs3826656 SNPs on AD risk have remained unclear.

    In their article, Chan et al. measured protein levels on the surface of peripheral monocytes from blood samples collected from 115 young subjects and 61 cognitively-intact aged individuals. The authors found that rs3865444C and rs3826656A alleles were associated with increased CD33 surface expression on peripheral monocytes.  However, rs3865444C and rs3826656A result in contrasting associations with susceptibility to late-onset AD. Therefore, it will be important to investigate whether the rs3826656A allele is also associated with increased CD33 levels in microglial cells in cognitively intact and AD brains, and how it impacts CD33 isoforms.

    Interestingly, Chan and colleagues found that the presence of the rs3865444C in CD33 was also associated with increased expression levels of TREM2 on the surface of peripheral monocytes. Further, they showed that suppressing CD33 signaling with a CD33-specific antibody resulted in decreased TREM2 surface expression levels in monocytes. It therefore will be important in future studies to dissect the molecular mechanisms underlying the cross-regulation between CD33 and TREM2 in peripheral monocytes and microglial cells, as well as in healthy aged versus AD brains. 

    Rare mutations in the TREM2 gene result in susceptibility to late-onset AD (Lill et al., 2015). Colonna and colleagues showed that TREM2 plays a beneficial role in AD by sustaining the microglial response to amyloid beta accumulation (Wang et al., 2015; Tanzi, 2015). In contrast, Jay et al. found that TREM2-positive brain macrophages play a detrimental role in mouse models of AD (Tanzi, 2015; Jay et al., 2015). In the new study, Chan et al. found that increased TREM2 mRNA levels were associated with greater amyloid load in the human prefrontal cortex, thus suggesting that increased TREM2 levels play a pathogenic role and lead to AD susceptibility. Therefore, it remains unclear whether increased or decreased TREM2 expression levels increase risk for late-onset AD (Tanzi, 2015; Jay et al., 2015). Future studies will be needed to resolve these discrepant results regarding the role of TREM2 in AD pathology. Meanwhile, the majority of the available data suggest that inhibiting CD33 remains a potentially useful strategy for ameliorating AD pathology.


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    . TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015 Mar 9;212(3):287-95. Epub 2015 Mar 2 PubMed.

    View all comments by Rudy Tanzi

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