Selective targeting of plaque‐associated microglia through systemic dendrimer administration in an Alzheimer’s disease model

Abstract

Abstract Background In Alzheimer?s disease (AD) microglia surround extracellular plaques and mount a sustained inflammatory response. Microglial elimination studies, as well as targeted microglial gene deletion studies, have suggested that this sustained microglial response to plaques contributes to the pathogenesis of the disease, including in plaque homeostasis, as well as contributing to synaptic and neuronal loss. The ability to specifically target plaque associated microglia would afford a powerful tool and potential therapeutic avenue. To that end, we sought proof of principle to target plaque associated microglia while leaving other microglia unaffected, via systemically administered Cy5 labelled hydroxyl dendrimers. Method To specifically target plaque associated microglia, we performed intraperitoneal injections with hydroxyl dendrimers conjugated to a Cy5 fluorophore into 5xFAD mice. Dendrimers are symmetric and highly branched molecules which are selectively endocytosed by reactive cells at sites of inflammation. To test whether we could alter plaque associated microglia phenotypes via peripheral drug administration, we next injected 5xFAD mice intraperitoneally with hydroxyl dendrimers conjugated to N-acetyl cysteine, OP-101, which has demonstrated ability to cause normalization of reactive microglia in several animal models. Result Here, we find that hydroxyl dendrimers are selectively taken up by reactive microglia surrounding plaques in the brain parenchyma of 5xFAD mice. The hydroxyl dendrimers co-localize with lysosomal (CD68+) puncta in the microglia and do not co-localize with neurons, astrocytes, or oligodendrocytes. The impact of OP-101 on microglia in the 5xFAD mouse as measured by RNAseq will also be presented. Conclusion These data provide evidence that hydroxyl dendrimers are specifically taken up by reactive microglia rather than other central nervous system cells. This study demonstrated that systemic administration of hydroxyl dendrimers is a sufficient tool to target plaque associated microglia, demonstrating the potential for hydroxyl dendrimer-based therapeutics in AD.