Establishing the role of MMP9 in amyloid-immunotherapy-induced ARIA

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ABSTRACT Anti-Ab immunotherapies such as aducanamab, donanemab, and lecanemab are either approved or awaiting approval for the treatment of Alzheimer’s disease (AD). While these agents hold great promise for the future of dementia treatment, their broad acceptance and use is hindered by significant concerns regarding safety. Almost two decades ago, our group and others first described microhemorrhages in the brains of transgenic mice resulting from anti-Ab immunotherapy. Since then, a substantial number of anti-Ab clinical trial subjects were also affected by vasogenic edema. Re-defined as amyloid-related imaging abnormalities (ARIA) of the edema- (ARIA-E) or hemorrhagic- (ARIA-H) types, ARIA events occurred in a third of aducanamab trial participants and remain a major concern surrounding the use of anti-Ab immunotherapy. We will test the novel hypothesis that anti-Ab immunotherapy triggers ARIA through inflammatory sequelae involving activation of the matrix metalloproteinase MMP9, degrading tight junction/basement membranes of vasculature inducing ARIA. Equipped with new technologies not available to us two decades ago (i.e. 7T MRI, intravital two-photon imaging, and single cell transcriptomics), we are poised to reveal mechanistic cause-and-effect relationships between Aβ-immunotherapy, MMP9, and ARIA-H using novel humanized Aβ mouse models (i.e. hAβ and hAβSAA mice). We propose using these novel mouse models to evaluate cellular, molecular, and functional changes resulting from immunotherapy using the antibody 3D6; a murine monoclonal antibody with an epitope like that of aducanamab. We propose three specific aims to test out hypothesis: Specific Aim 1: Define neurovascular and neuroimmune responses to Ab immunotherapy in the humanized-Ab mouse model. Specific Aim 2: Determine the role of MMP9 in ARIA development resulting from Ab immunotherapy. Specific Aim 3: Evaluate the potential of MMP9 inhibition to eliminate ARIA.