Evaluation of CD33 as a genetic risk factor for Alzheimer ’s disease

AbstractIn 2011, genome-wide association studies implicated a polymorphism nearCD33 as a genetic risk factor for Alzheimer ’s disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found thatCD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying theCD33 genetic association with Alzheimer ’s disease. The allele that protects from Alzheimer’s disease acts predominately to increase aCD33 isoform lacking exon 2 at the expense of the prototypic, full-lengthCD33 that contains exon 2. Since this exon encodes the sialic acid ligand-binding domain, the finding that the loss of exon 2 was associated with decreased Alzheimer ’s disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer’s disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associa ted with Alzheimer’s disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand-binding domain represents a gain of function variant that reduces Alzheimer’s disease risk.
Source: Acta Neuropathologica - Category: Neurology Source Type: research