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bioRxiv · 10.64898/2026.09.10.750803

Semaphorin 3G (SEMA3G) is a highly selective marker of cerebral amyloid angiopathy

Balcomb, K.·Buchanan, J.·Strobbe, A.·Claus, D.·Faustin, A.·Schneider, J.·Wisniewski, T.·Sunde, M.·Drummond, E.
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Abstract

Biomarkers of cerebral amyloid angiopathy (CAA) are critically needed. We recently identified semaphorin 3G (SEMA3G) as a novel protein selectively enriched in CAA. Here, we aimed to determine if SEMA3G was a selective marker of CAA in a large cohort of human brain tissue spanning multiple neurodegenerative diseases and three brain regions, and to determine if SEMA3G directly interacts with amyloid beta (A{beta}). Multiplexed immunofluorescence showed that SEMA3G significantly accumulated only in CAA+ blood vessels in the brain in all cases. We also showed that SEMA3G preferentially associated with A{beta}40, A{beta}pS8 and A{beta}pE3, but not A{beta}42. Thioflavin T assays and transmission electron microscopy showed that SEMA3G directly interacted with A{beta} and slowed A{beta} aggregation in vitro, and that this effect was more pronounced for A{beta}40 than A{beta}42. Together our results demonstrate that SEMA3G is a highly specific marker of CAA in the brain.

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Balcomb, K., Buchanan, J., Strobbe, A., Claus, D., Faustin, A., Schneider, J., Wisniewski, T., Sunde, M., Drummond, E.. 2026-09-16. Semaphorin 3G (SEMA3G) is a highly selective marker of cerebral amyloid angiopathy. https://doi.org/10.64898/2026.09.10.750803

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