Microglia are the brain resident immune cells that maintain brain homeostasis by responding to cytokines and eliminating substances by phagocytosis. Microglial activation and phagocytotic clearance of aggregated amyloid ß (Aß) and tau aggregates limits Alzheimer’s disease (AD) pathology. There is an urgent need to elucidate the mechanisms that promote these actions and to develop novel approaches to control AD pathology. We recently discovered that Sulf2, an extracellular heparan sulfate (HS) sulfatase, selectively suppresses microglial response to interleukin 4, a cytokine that restricts microglia activation. Furthermore, our preliminary result showed that Sulf2 facilitated microglial phagocytotic clearance of Aß deposits ex vivo. The aims of the proposed project are: i) to clarify the molecular mechanism underlying Sulf2 effects on these microglia functions and ii) to investigate whether HS remodeling by Sulf2 could reduce Aß load and tau aggregates in AD brain in vivo by facilitating sustained and controlled microglial phagocytosis activity over time. The HS compositions and structure of HS S-domains present in Sulf2-transduced microglial cell line and primary mouse microglia; in the brains of microglia-specific Sulf2 transgenic/J20 hAPP-Tg and P301S tau-Tg AD model mice; in AD patient brains, will be determined by state-of-the-art methods, including mass spectrometry-based methods and a protein nanopore oligosaccharide sequencing technique. RNA-seq transcriptome analysis will be also performed for these microglial cells and AD model mouse brains. We will evaluate AD pathogenesis in vivo in these Sulf2-transgenic AD model mice. The partners’ expertise in glycoscience, neurology, and structural biology strengthens the accomplishment of the proposed project. As a whole, our ultimate goal is to develop a novel strategy for AD treatment with the idea of contributing to better health and well-being as well as social and economic welfare.