Role for Semaphorin 3A in Microglial Activation and Alzheimer's Disease

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In addition to the hallmark pathological features, such as β-amyloid peptide (Aβ) plaques, tangles and widespread neuronal loss, there are profound inflammatory changes in the AD brain. Microglia, the brain-resident myeloid cells, are linked closely to all pathological cascades including amyloid, tau and neuroinflammatory changes. Genome-wide association studies (GWAS) have revealed that known AD risk genes are preferentially or selectively expressed in microglia. Our recent computational and cell biological investigations revealed that crosstalk interactions between excitatory neurons and microglia are predicted to modulate AD risk genes and to be mediated through several ligand-receptor pairs. Notably, two neuronal semaphorins, originally discovered as axonal guidance factors, were linked to microglial receptors, including semaphorin 6D (SEMA6D) and semaphorin 3A (SEMA3A). Using a human iPSC-derived microglial-like model (iMGL), we found that SEMA3A strongly promotes β-amyloid uptake as compared to other phagocytic substrates, such as synaptosomes. SEMA3A-induced phagocytosis was preserved in TREM2-depleted iMGLs, suggesting that SEMA3A-associated microglial activation occurs independently of TREM2. Surprisingly, RNA-seq analysis revealed that SEMA3A induces the gene expression profile that highly resembles that of disease- associated microglia (DAM). Building on our interesting preliminary results, the overall goal of the current project is to determine the functional role and mechanistic basis for SEMA3A-mediated regulation of microglial activation in AD. The successful completion of our proposed research will unveil a hitherto unexplored connection between SEMA3A signaling in microglial and AD pathobiology, and lay the foundation for therapeutic strategies to modulate microglial activities inAD. Project Number: 1R21AG091800-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: TAE-WAN KIM | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $452,375 | Activity Code: R21 | Study Section: Cellular and Molecular Biology of Glia Study Section[CMBG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11238212