Malik M, Simpson JF, Parikh I, Wilfred BR, Fardo DW, Nelson PT, Estus S. CD33 Alzheimer's Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing. J Neurosci. 2013 Aug 14;33(33):13320-5. PubMed.
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Van Andel Institute
Even though the mechanism proposed by the authors is just a model (no experiments were done to actually demonstrate the involvement of sialic acids in the pathway), the identification of a potential functional polymorphism in linkage disequilibrium with a single nucleotide polymorphism (SNP) identified by genome-wide association studies(GWAS) is of great interest.
By design, the probability of GWAS identifying the real variant associated with a disease risk is very small. On top of this, a large proportion of the identified SNPs are located in gene deserts, non-coding gene regions, or are intergenic. This indicates that a large part of the genetic risk for common diseases is unrelated to coding variations and most probably comes from gene expression changes.
The authors have designed a clever way to assess the role of one of these variants and they show that not only is CD33 expression increased in AD, but they provide a functional SNP linked with the GWAS SNP that is involved with differential splicing of exon 2 (which encodes the IgV domain).
These and other recent results clearly show that the latest International Genomics of Alzheimer’s Project CD33 risk association needs to be re-evaluated and, once again, puts microglial pathways in the spot for Alzheimer's disease.
It will definitely be important to test rs12459419 in big cohorts of cases and controls.
Massachusetts General Hospital and Harvard Medical School
The article by Malik and colleagues offers new insights into the genetics of CD33, a gene that we first reported as a risk factor for Alzheimer’s disease (AD) in 2008 (Bertram et al., 2008). CD33 is a sialic acid-binding protein that we recently found to be expressed in microglial cells in the aging human brain (Griciuc et al., 2013). There, it inhibits the clearance of amyloid β, and promotes the deposition of Aβ in plaques, which are major pathological hallmarks of AD. We have previously shown that the CD33 variant, rs3865444, which protects against AD is associated with reduced CD33 microglial expression. Our finding that CD33 inactivation in mice leads to reduced amyloid pathology in the brain further suggests a critical role for CD33 in AD pathogenesis. However, the molecular mechanisms underlying the protective effect of the rs3865444 mutation has remained hidden.
In their article, Malik et al. characterize another CD33 variant, the missense substitution, rs12459419, that is in close proximity to the rs3865444 mutation; these two mutations are co-inherited. The authors suggest that rs12459419 promotes the splicing of CD33 RNA into an alternative mRNA version which lacks the sialic acid binding domain. As such, the truncated CD33 protein would be unable to carry out its cellular functions that are regulated by sialic acid binding.
Our recent study suggested a critical role for the sialic acid-binding domain of CD33 based on its inhibitory effect on amyloid beta uptake and clearance by microglia; a genetically-engineered mutant CD33 version lacking the sialic acid-binding domain is no longer capable of inhibiting amyloid beta clearance (Griciuc et al., 2013). These results are consistent with those of Malik et al. showing that the rs12459419 variant may confer protection against AD by promoting the production of a functionally defective CD33 variant in the human brain - one resembled by the genetically-engineered version we tested in cultured microglial cells. These are important findings that provide further support for the critical role of sialic acids in modulating the activity of CD33 in the aging brain. They also suggest that disrupting the interaction between CD33 and sialic acids could represent a powerful therapeutic strategy to inhibit the progression of AD pathology, a point that we also emphasized in our recent study.
Together, these findings suggest that CD33 and its role in microglial cells is clearly emerging as a central player in the pathogenesis of AD (see Figure) and opens new therapeutic avenues for treating and preventing this devastating disease.
Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008 Nov;83(5):623-32. PubMed.
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013 May 22;78(4):631-43. PubMed.
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