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Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer's disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate\u2010associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of <jats:italic>O<\/jats:italic>\u2010 and <jats:italic>N<\/jats:italic>\u2010linked glycans in autopsy\u2010confirmed AD post\u2010mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell\u2010to\u2010cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both <jats:italic>N<\/jats:italic>\u2010 and <jats:italic>O<\/jats:italic>\u2010linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater <jats:italic>N<\/jats:italic>\u2010sialylation of the A\u03b2 plaque microenvironment compared with <jats:italic>O<\/jats:italic>\u2010sialylation. Plaque\u2010associated microglia displayed the most intense <jats:italic>N<\/jats:italic>\u2010sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of <jats:italic>N<\/jats:italic>\u2010 and <jats:italic>O<\/jats:italic>\u2010sialylation between cored and diffuse A\u03b2 plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in <jats:italic>N<\/jats:italic>\u2010sialylation and no influence of <jats:italic>O<\/jats:italic>\u2010sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.<\/jats:p>","DOI":"10.1111\/bpa.13267","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:58:55Z","timestamp":1715302735000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4729-2712","authenticated-orcid":false,"given":"Caitlyn","family":"Fastenau","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Texas Health Science Center San Antonio  San Antonio Texas USA"},{"name":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases 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