Controversies about the subcellular localization and mechanisms of action of the Alzheimer's disease-protective CD33 splice variant.
Genome-wide association studies (GWAS) identified an allele of the microglial CD33 (Siglec-3) cell surface receptor that protects against Alzheimer's disease (AD). Protected individuals express less full-length CD33 and more alternatively spliced D2-CD33 lacking the amino-terminal sialoglycan-ligand-binding domain. The mechanism by which D2-CD33 reduces AD risk is unknown. A recent excellent review [1] concluded that the protective allele may act via gain of function, with excess cell surface D2-CD33 reducing risk via “a higher propensity toward microglial activation through mechanisms similar to the well-recognized functions of TREM2 and its co-receptor, DAP12”. However, our earlier study [8] showed that D2-CD33 (a.k.a. CD33m or CD33ΔV-Ig) is diverted to intracellular peroxisomes (consistent with a conserved peroxisomal targeting signal in the cytosolic tail).
Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. Center for Academic Research and Training in Anthropogeny, University of California, San Diego, San Diego, USA. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. Center for Academic Research and Training in Anthropogeny, University of California, San Diego, San Diego, USA. American University of Ras Al Khaimah (AURAK), Ras Al Khaimah, UAE. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. Center for Academic Research and Training in Anthropogeny, University of California, San Diego, San Diego, USA. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. Center for Academic Research and Training in Anthropogeny, University of California, San Diego, San Diego, USA. BioLegend Inc., San Diego, CA, USA. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. University of Prince Edward Island, Charlottetown, Canada. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, San Diego, USA. a1varki@ucsd.edu. Center for Academic Research and Training in Anthropogeny, University of California, San Diego, San Diego, USA. a1varki@ucsd.edu.
