Researchers here explore CD33 as a possible target for the development of Alzheimer's disease treatments. The protein suppresses the ability of microglia in the brain to ingest and dispose of amyloid. This, in principle, will cause issues over the long term by promoting the presence of amyloid, leading to neural dysfunction and chronic inflammation in the brain. The work here is also interesting as an illustration of the complexities of trying to model the processes of Alzheimer's disease in mice, a species that doesn't normally suffer any of the relevant underlying mechanisms that produce the condition. Previous research proceeded on the basis that the mouse version of CD33 behaved in much the same way as the human version, which turns out not to be the case.
The strong genetic link between variants of CD33 and Alzheimer's disease (AD) susceptibility suggests that targeting the common risk allele of CD33, which preferentially encodes the longer human isoform of (hCD33M) containing its glycan-binding domain, could be a treatment strategy in neurodegenerative disease. To better understand if targeting CD33 in AD is a viable option, a better grasp is needed on the role CD33 plays in modulating the function of microglia. Our findings demonstrate that expression of the long isoform of hCD33 (hCD33M) alone is sufficient to repress phagocytosis in both monocytes and microglia. We have created transgenic mice expressing hCD33M, and these will be a valuable tool for future studies addressing the role of hCD33 in modulating plaque accumulation as well as pre-clinical testing of therapeutics aimed at targeting hCD33.
Divergent features between human CD33 (hCD33) and mouse CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. In mouse derived macrophages and monocytes, uptake of cargo - including aggregated amyloid - is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis.
Accumulation of aggregated amyloid drives the formation of amyloid plaques and mouse models to study human genetic factors that modulate this process in vivo have been widely used. Our studies suggest that mCD33 may not be an appropriate surrogate for studying hCD33. We demonstrate that transgenic expression of hCD33M in the microglial cell lineage inhibits phagocytosis; these hCD33M transgenic mice should provide a valuable model to test the role of hCD33M in regulating plaque accumulation in vivo, which is currently being tested in ongoing studies in our laboratory. Indeed, establishing a good mouse model to study hCD33 is critical for both better understanding AD pathology and also testing therapeutics aimed at controlling microglial cell function by targeting hCD33M.