Anti-medin immunotherapy for vascular aging and related dementias

点击翻译按钮获取中文摘要

ABSTRACT Age is the most important risk factor for cardio-cerebrovascular diseases (CVD) and dementia disorders. Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia disorders, including Alzheimer's disease (AD) and AD-related dementias (ADRD) such as vascular dementia (VaD). Indeed, unbiased data-driven analyses showed that vascular dysfunction is the earliest and strongest brain pathology associated with late onset AD. There is growing evidence that medin, a 50-amino acid peptide that forms one of the most common yet least studied human amyloidoses, is an important driver of vascular aging pathologies. We and others showed that vascular medin burden was associated with VaD, AD and aortic aneurysms. Medin, a cleavage product of milk fat globule-EGF factor 8 protein (MFGE8), accumulates in vessels with aging, causes endothelial dysfunction through oxidative and nitrative stress and induces endothelial pro- inflammatory activation that could initiate neuroinflammation. Knockout of MFGE8 domain containing medin prevented cerebrovascular medin amyloid formation and restored cerebrovascular function. We designed and produced an immunogen modified from the aggregation-prone C terminus of medin to be used as anti-medin vaccine and 3 monoclonal antibodies (mAbs) that have high medin affinity. Our overall goal is to evaluate anti- medin immunotherapy using medin vaccination (Aim 1) and anti-medin mAbs (Aim 2) to attenuate or prevent medin-induced vascular dysfunction and neurovascular pathology in aging C57BL/6 mice and in senescence accelerated mouse-prone 8 (SAMP8) mice. Aim 1 is to develop and test the benefit of anti-medin vaccination in preventing cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. We will first determine an optimal vaccination regimen and then test the efficacy of that regimen. Aim 2 is to develop and pilot test anti-medin mAb immunotherapy to attenuate medin-induced cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. First, we will determine which mAb (19H1, 6F2 and 13B7) will have the best effect in reversing medin-induced endothelial cytotoxicity. Next, we will do pilot feasibility in vivo testing of the ideal dosing of anti-medin mAbs to reduce cerebrovascular medin and preserve cerebrovascular and cognitive function. The proposal is innovative and paradigm-changing in potentially establishing medin as a new target for vascular disease and dementia, and anti-medin immunotherapy as a potential new treatment approach for vascular aging and resulting pathologies.