Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer’s disease mouse model​.

Background: In Alzheimer’s disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. Methods: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). Results: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. Conclusions: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs. We took 12-month old WT, WT/D45113, 5xFAD, and 5xFAD/D45113 mice and performed bulk RNA Sequencing on the hippocampi to assess the differences in gene expression between each group