Blood vessel abnormalities in the brain, including leaks in the blood brain barrier (BBB), play a significant role in Alzheimer’s disease.  During normal injuries, bleeding causes enzymes to trim the blood plasma protein fibrinogen, forming fibrin.  The conversion of fibrinogen to fibrin is essential for blood clot formation, but also changes the structure of the protein, exposing a sequence that activates a set of inflammatory cells.  Normally in the presence of high proteolytic activity fibrin in blood clots is slowly degraded as healing progresses and inflammation subsides.  However, in the AD brain proteolytic activity is perturbed resulting in sustained fibrin deposition. Vascular alterations occur early in dementia and Alzheimer’s disease. The combination of the underlying vascular defect and the subsequent production   of fibrin results in chronic neuroinflammation leading to nerve damage and the progressive cognitive decline characteristic of Alzheimer’s disease. The characterization of  the underlying disease biology found in Alzheimer’s disease clearly defines an amyloid-independent vascular mediated mechanism.  A drug that blocks fibrin mediated inflammation but does not inhibit its capacity for blood clotting would be of high therapeutic value.  Furthermore, an imaging biomarker for sensitive and direct detection of increased vascular permeability has not been developed. Studies revealed that fibrin is associated to amyloid plaques found in the brains of Alzheimer’s patients, and this fibrin-amyloid complex may impact the normal enzymatic degradation fibrin.   Detection of fibrin is ideally positioned as a molecular indicator of early blood vessel abnormalities and the first stages of Alzheimer’s disease, while blocking the interaction of fibrin with inflammatory cells early could slow or halt disease progression.  Because fibrin is a polymer consisting of multiple fibrinogen molecules, until recently all antibodies that recognized fibrin sequences also recognized fibrinogen circulating in the blood.  Therefore, imaging techniques based on anti-fibrinogen antibodies would light up the entire circulatory system, compromising sensitivity and bioavailability of fibrin detection in the brain.  A recent discovery by Dr. Katerina Akassoglou, academic co-founder of MedaRed, Inc., identified mouse antibody 5B8 which binds to a sequence that is only exposed when fibrinogen unfolds into fibrin, and therefore is specific for fibrin deposits.  Preliminary experiments showed that 5B8 antibody could detect fibrin deposits in mouse models of Alzheimer’s disease and block fibrin-induced activation of inflammatory cells and subsequent neuronal loss.  The goals of this proposal are to advance preclinical development of a humanized version of 5B8 (MRD205) and to test forms of antibody 5B8 for imaging of fibrin deposits in the brain.  If successful, these studies will lead to clinical trials of appropriate forms of 5B8 as an imaging agent for brain vascular damage that could potentially identify early stages of Alzheimer’s and as a therapeutic antibody to treat the disease.