Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy
- 1Department of Neurology, Mass General Brigham, Harvard Medical School, Charlestown, MA, USA
Abstract
Anti-amyloid {beta} (A{beta}) immunotherapy improves cognitive outcomes in Alzheimer's disease (AD) but is associated with amyloid-related imaging abnormalities (ARIA), through poorly understood mechanisms. To define how anti-A{beta} antibodies acutely engage brain immune and vascular compartments, we developed a longitudinal in vivo two-photon imaging platform to track microglial dynamics, peripheral immune cell recruitment, and vascular responses in APP/PS1 mice. Anti-A{beta} antibodies, including aducanumab and lecanemab, rapidly initiated microglial activation and spatial reorganization within 24 hours of dosing, with recruitment to plaque-associated regions, stabilizing plaque growth. Aducanumab and lecanemab also triggered a rapid and transient cerebrovascular immune response characterized by rolling and adhesion of peripheral immune cells along leptomeningeal vessels, accompanied by endothelial activation. Immune cell characterization revealed recruitment of innate immune cells (Iba1Ki67 monocytes and Ly6G neutrophils) and proliferative CD3 T cells into the vascular compartment following treatment. Prophylactic treatment with high-dose dexamethasone reduced the number of adherent cells without affecting microglial activation. Depletion of brain-resident immune cells similarly reduced peripheral immune cell recruitment, supporting their contribution to leukocyte recruitment. Postmortem brain tissue from an AD patient treated with lecanemab showed higher proliferation-associated monocyte signature scores, suggesting translational relevance to the proliferative myeloid response observed in our mouse models. These findings demonstrate that anti-A{beta} immunotherapy rapidly initiates a coordinated central and peripheral immune response at the leptomeningeal interface. These early immune-vascular interactions represent a plausible initiating mechanism for ARIA and provide a mechanistic framework to guide strategies for mitigating ARIA risk
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BibTeX
@misc{algamal2026brainresident,
title = {{Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy}},
author = {M. Algamal and S. Yokomizo and W. Ndambakuwa and S. Abdallah and M. V. Sanchez-Mico and R. Gillani and P. da Silva and A. Rajput and L. Palanivelu and Y. Lee and K. R. Walsh and S. Kumar and K. Kilic and J. El Khoury and S. Izzy and M. G. Kozberg and B. J. Bacskai},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749938},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749938v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy
AU - M. Algamal
AU - S. Yokomizo
AU - W. Ndambakuwa
AU - S. Abdallah
AU - M. V. Sanchez-Mico
AU - R. Gillani
AU - P. da Silva
AU - A. Rajput
AU - L. Palanivelu
AU - Y. Lee
AU - K. R. Walsh
AU - S. Kumar
AU - K. Kilic
AU - J. El Khoury
AU - S. Izzy
AU - M. G. Kozberg
AU - B. J. Bacskai
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749938
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749938v1
AB - Anti-amyloid {beta} (A{beta}) immunotherapy improves cognitive outcomes in Alzheimer's disease (AD) but is associated with amyloid-related imaging abnormalities (ARIA), through poorly understood mechanisms. To define how anti-A{beta} antibodies acutely engage brain immune and vascular compartments, we developed a longitudinal in vivo two-photon imaging platform to track microglial dynamics, peripheral immune cell recruitment, and vascular responses in APP/PS1 mice. Anti-A{beta} antibodies, including aducanumab and lecanemab, rapidly initiated microglial activation and spatial reorganization within 24 hours of dosing, with recruitment to plaque-associated regions, stabilizing plaque growth. Aducanumab and lecanemab also triggered a rapid and transient cerebrovascular immune response characterized by rolling and adhesion of peripheral immune cells along leptomeningeal vessels, accompanied by endothelial activation. Immune cell characterization revealed recruitment of innate immune cells (Iba1Ki67 monocytes and Ly6G neutrophils) and proliferative CD3 T cells into the vascular compartment following treatment. Prophylactic treatment with high-dose dexamethasone reduced the number of adherent cells without affecting microglial activation. Depletion of brain-resident immune cells similarly reduced peripheral immune cell recruitment, supporting their contribution to leukocyte recruitment. Postmortem brain tissue from an AD patient treated with lecanemab showed higher proliferation-associated monocyte signature scores, suggesting translational relevance to the proliferative myeloid response observed in our mouse models. These findings demonstrate that anti-A{beta} immunotherapy rapidly initiates a coordinated central and peripheral immune response at the leptomeningeal interface. These early immune-vascular interactions represent a plausible initiating mechanism for ARIA and provide a mechanistic framework to guide strategies for mitigating ARIA risk
ER -