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Spatial transcriptomics reveals microglial mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients

ABSTRACT: Current Alzheimer's disease (AD) therapies immunize patients against amyloid-β (Aβ). Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Leveraging spatial transcriptomics (ST), we mapped the effects of both active and passive Aβ immunization in the AD brain. Comparing actively immunized AD brains with non-immunized AD patients and controls without neurologic disease, we uncovered unique microglial states associated with Aβ clearance. Through high-resolution ST and single-cell RNA sequencing (scRNAseq), we further analyzed the pathways involved in Aβ removal following lecanemab treatment, identifying spatially distinct microglial responses. We discovered a significant upregulation of Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Apolipoprotein E (APOE) in microglia clearing Aβ, a response common to both active and passive immunization. These findings offer new insights into the transcriptional mechanisms driving Aβ clearance, advancing our understanding of Aβ-targeted therapies and identifying new potential therapeutic targets in AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263034 | GEO | 2025/03/03

REPOSITORIES: GEO

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Spatial transcriptomics reveals microglial mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients

Project description:Current Alzheimer's disease (AD) therapies immunize patients against amyloid-β (Aβ). Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Leveraging spatial transcriptomics (ST), we mapped the effects of both active and passive Aβ immunization in the AD brain. Comparing actively immunized AD brains with non-immunized AD patients and controls without neurologic disease, we uncovered unique microglial states associated with Aβ clearance. Through high-resolution ST and single-cell RNA sequencing (scRNAseq), we further analyzed the pathways involved in Aβ removal following lecanemab treatment, identifying spatially distinct microglial responses. We discovered a significant upregulation of Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Apolipoprotein E (APOE) in microglia clearing Aβ, a response common to both active and passive immunization. These findings offer new insights into the transcriptional mechanisms driving Aβ clearance, advancing our understanding of Aβ-targeted therapies and identifying new potential therapeutic targets in AD.

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Spatial transcriptomics reveals microglial mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients

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Spatial transcriptomics reveals neuroimmune mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients.

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