Genome-wide association studies have identified and validated several genes, such as CD33, associated with AD susceptibility that directly implicate the innate immune system. CD33 is a sialic acid binding protein expressed on the surface of myeloid cells, and higher CD33 expression levels in the brain have been associated with more advanced cognitive decline and AD. We demonstrated that individuals with the Alzheimer’s disease associated rs3865444CC risk genotype have increased expression of full-length CD33, the isoform containing the sialic acid binding domain, on the surface of their monocytes compared to those with the rs3865444AA protective genotype. The risk allele is also associated with diminished internalization of amyloid-β1-42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of human microglia with small, thick processes, and a rounded morphology. Using a crosslinking strategy combined with mass spectrometry we identified immune cell specific sialic acid-dependent and independent CD33 binding partners. Using proximity ligation assays, we have validated these results in vitro as well as in situ. For one of the binding partners, we confirmed that the CD33 ITIM domain was also involved in the interaction. Using a known inhibitor for the binding partner, we can disrupt the interaction. In conclusion, we have identified and validated the functional relevance of CD33 binding partners that are specific to the sialic acid binding domain of CD33, the domain that is modulated by the Alzheimer’s disease association.

CD33: From Alzheimer’s disease GWAS to therapeutic target

2019 Fall National Meeting

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