Background: Recent advances in Alzheimer's disease (AD) therapeutics involve immunization against amyloid-β (Aβ). Post-mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown.
Method: Here, we utilized a novel spatial proteogenomics approach to study brain tissues from 13 AD patients immunized with Aβ. We compared these actively immunized patient brains to tissues from non-immunized AD patients and non-neurologic disease controls. Additionally, we used spatial proteogenomics and single-cell RNA sequencing technologies to investigate the effects of lecanemab, a passive anti-Aβ drug.
Result: We reveal the transcriptomic neuroimmune response in the Aβ plaque microenvironment following anti-Aβ immunization. This response is characterized by an increase in genes associated with the TREM2-APOE axis in microglia of the immunized AD cortex.
Conclusion: Altogether, our data uncover immediate and lasting neuroimmune responses in the AD brain induced by active and passive Aβ vaccination.
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| http://dx.doi.org/10.1002/alz.088081 | DOI Listing |
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Article Synopsis
- The study investigates how neurodegenerative disorders, particularly Alzheimer's disease, affect brain microenvironments by analyzing brain tissue lesions associated with amyloid-β and hyperphosphorylated tau.
- Researchers used the advanced 10x Genomics Visium Spatial Proteogenomics platform to explore gene expression changes in post-mortem human brains, specifically in the inferior temporal cortex during late-stage Alzheimer's.
- The findings offer insights into molecular processes linked to brain pathology, provide a framework for analyzing spatial gene expression, and deliver accessible interactive resources for the scientific community to explore related datasets.
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