Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Alzheimer's disease (AD) therapies increasingly use amyloid-β (Aβ) immunization.
• Microglial responses are well-studied, but astrocytes also accumulate at Aβ plaques.
• Astrocytes may play a crucial role in Aβ clearance during immunotherapy.

Purpose of the Study:

• To investigate how astrocyte phenotypes change in response to Aβ immunization in AD.
• To determine the contribution of these altered astrocytes to Aβ clearance.

Main Methods:

• Single-cell RNA sequencing and spatial transcriptomics on post-mortem AD brain tissue.
• Analysis of 16 AD patients (10 immunized, 6 controls).
• Identification and mapping of astrocyte states, particularly those near Aβ plaques.

Main Results:

• A distinct astrocyte population with upregulated CHI3L1 and reactive markers emerged after AN1792 and lecanemab immunization.
• These CHI3L1-expressing astrocytes were found at microglia-targeted Aβ plaques following lecanemab treatment.
• Further analyses are ongoing to characterize astrocyte morphology, protein expression, and Aβ uptake.

Conclusions:

• A unique astrocyte phenotype, characterized by high CHI3L1 expression, is induced by Aβ immunization in AD.
• This astrocyte state may be influenced by microglia at Aβ plaques and contribute to Aβ clearance.
• Findings reveal distinct astrocyte responses to Aβ immunotherapy, clarifying their role in treatment efficacy.