Sanchez-Mico, M. V. | Search bioRxiv

bioRxiv2026

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

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

neuroscience↗

bioRxiv2022

Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid beta aggregates in vivo in a mouse model of Alzheimer's disease

BackgroundReactive oxidative stress is a critical player in the amyloid beta (A{beta}) toxicity that contributes to neurodegeneration in Alzheimers disease (AD). Mitochondrial damage, observed in AD, is one of the main sources of reactive oxygen species. Although A{beta} causes neuronal mitochondria-associated reactive oxidative stress in vitro, this has never been directly observed in the in vivo living brain. Here, we tested whether A{beta} plaques and soluble oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether the neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease, and performed intravital multiphoton microscopy of neuronal mitochondria and A{beta} plaques. ResultsFor the first time, we demonstrated by direct observation exacerbated mitochondrial oxidative stress in neurons after both A{beta} plaque deposition and direct application of soluble oligomeric A{beta} onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. ConclusionsConsidering these results, mitochondria-targeted compounds hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

neuroscience↗