TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAbSAA mouse model

The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer’s disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development. This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes. In this study, we established ARIA-H pathology in a humanized mouse model (hAβSAA) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region. We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.