Microglial Glycosylation
Microglia are the resident immune cells of the brain. These brain protectors and cleaners interact with other cells, the tissue environment, and in the setting of disease, neuropathologies, through protein receptors on the surface of the microglia. One class of receptors are known as “Siglecs”, or sialic acid-binding immunoglobulin-like lectins. These receptors recognize a post-translationally modified sugar molecules, sialic acid, which can in turn either activate or inhibit microglial immune responses, including phagocytosis. Identifying what pathologies and/or cells are sialylated in Alzheimer’s disease and other related neurodegenerative disorders could help us better understand how microglia interact with each other and/or misfolded and aggregated pathological proteins as well as potentially modify microglia to induce clearance of these protein aggregates.
For her thesis studies, Caitlyn Fastenau (in co-sponsorship with the Hopp lab) measured alpha-2,6 (“B” & “C”) and alpha-2,3 (“E” & “F”) sialic acid in the brains of an Alzheimer’s disease mouse model (5XFAD; “B” & “E”) and wild-type controls (“C” & “F”). Caitlyn found high expression of alpha-2,6 in the brains of the Alzheimer’s disease mice, but not in control mice. Follow-up studies revealed this sialylation was found on the surface of microglia surrounding beta-amyloid plaques (but not on the plaques themselves). An enzyme called Neuraminidase-1 cuts alpha-2,6 sialic acid bond, so Caitlyn tested a drug that inhibits Neuraminidase-1 (oseltamivir) to study how beta-amyloid plaques and behavior of the mice is altered (although, no differences were observed).
To learn more, check out our 2023 GeroScience study.
With this observation in mice, we next explored human postmortem brain tissue from brain donors with Alzheimer’s disease and related neurodegenerative disorders to determine whether plaque-associated microglia were similarly sialylated. We discovered microglia associated with beta-amyloid-positive plaques express alpha-2,6 sialic acid (N-linked sialylation). Microtubule-associated protein tau-positive neurofibrillary tangle pathology was also slightly associated with increased alpha-2,6 sialic acid expression. Additionally, we adapted historic mucin stains of O-linked glycosylation [Periodic acid Schiff-Alcian Blue stains (“D” column) & high iron diamine stains (“E” column)] to demonstrate cored plaques express sulfonated O-linked sialic acid modifications. With the knowledge that plaque-associated microglia are sialylated, we are further assessing where this modification is being made and how it impacts the identity and function of these microglial cells.
To learn more, check out our 2024 Brain Pathology study.
Through ongoing collaborations with the Hopp laboratory, we continue to explore the role of glycosylation (particularly sialylation) in brain aging and neurodegenerative diseases. These studies include assessing other neuropathologies (including cerebral amyloid angiopathy) and further/deeper profiling of microglia.