Project Summary/Abstract (Stream Biomedical) Dementia is estimated to effect nearly 50 million people worldwide. Alzheimer?s Disease (AD) is the leading cause of dementia and 6th leading cause of death in the United States. The social and economic impact of AD and related dementias is profound: 1 in 10 people over the age of 65 have AD, and 16 million Americans provide unpaid care for friends or family members with AD or related dementias, at a cost of $323 billion dollars. This burden is also heavily weighted on women, who comprise nearly 65% of all patients. Death from AD is increasing at a rate 10- fold higher than heart disease, and early diagnosis and/or improved therapeutics for AD could result in projected cost-saving of $7.9 trillion dollars. There are no proven therapies for AD, and there is a great unmet need for therapies that inhibit the underlying mechanisms or halt disease progression. Importantly, AD is identified as sharing many neurovascular pathologies with vascular dementias (VaD), and stroke and other neurovascular conditions are significant risk-factors for developing AD. Stream Biomedical is commercializing a therapeutic protein, recombinant human perlecan domain V (rDV), which has been shown in vitro and in small animals to be angiogenic, anti- inflammatory, neuroprotective, and gliomodulatory. rDV inhibits amyloid-induced toxicity and improves cell viability in neurons critically affected by AD, as well as in brain microvascular endothelial cells. Post-stroke application in rodents results in profound improvements in cellular and functional outcomes. Preliminary studies investigating rDV as an anti-amyloid agent suggest that rDV may exert powerful therapeutic effects in AD. rDV has been shown to protect neurons and endothelial cells from amyloid-induced toxicity and modulate the activity of endothelial cells and astrocytes in a synergistic manner that accelerates migration toward locus of injury while reducing chronic inflammation and glial scar formation. in vitro studies of isolated brain microvasculature have demonstrated that rDV induces a p-gp-mediated increase in amyloid transmembrane clearance into the lumen. The next target therapeutic applications for rDV are AD and VaD, to investigate its potential as a subchronic intervention for combating cellular and molecular pathologies and improving cognitive function. The developmental objectives of this translational phase 1 proposal are to conduct pilot studies to investigate and identify potential therapeutic action and bioactivity in the context of AD and VaD, investigate age-specific variability, establish foundation for dose-range finding studies, and provide insight on interaction of peripheral systems through parallel ex-vivo and in-vivo studies.