Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy

Anti-Aβ immunotherapy, used to enhance cognitive function in Alzheimer's disease, inadvertently triggers significant immune responses within the brain's blood vessels. To better understand this process, researchers developed an imaging technique to observe microglial activity, peripheral immune cell movement, and vascular changes in mice with Alzheimer's-like conditions.

Upon administering anti-Aβ antibodies like aducanumab and lecanemab, microglial activation and reorganization occurred within 24 hours, primarily around plaque regions, and accelerated plaque growth.

These antibodies also initiated a brief immune response in the cerebrovascular system, characterized by rolling and adhesion of peripheral immune cells to leptomeningeal vessels. This was coupled with endothelial activation, marking the initial steps of a larger immune-vascular interaction. The immune makeup of this response included innate immune cells such as Iba1Ki67 monocytes and Ly6G neutrophils, as well as proliferative CD3 T cells entering the vascular compartment after treatment.

Interestingly, the study found that prophylactic use of high-dose dexamethasone could decrease the number of adherent immune cells without impacting the microglial activation. Additionally, blocking these brain-resident immune cells also diminished peripheral immune cell recruitment, demonstrating their crucial role in the leukocyte recruitment process.

Postmortem analysis of a human brain treated with lecanemab revealed elevated proliferation-associated monocyte scores, implying that these findings could have implications for the proliferative myeloid response seen in human Alzheimer's patients.

These discoveries establish that anti-Aβ immunotherapy induces a swift, comprehensive immune response at the leptomeningeal junction, potentially serving as the starting point for Amyloid-Related Imaging Abnormalities (ARIA). This provides a solid foundation for developing strategies to minimize the risk of ARIA.