Controversies about the subcellular localization and mechanisms of action of the Alzheimer's disease-protective CD33 splice variant

Excerpt

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). …