Recent studies have documented important roles for heparan sulfate proteoglycans (HSPGs) in aging and development of the nervous system. HSPGs are proposed to regulate processes as diverse as neural cell differentiation, cell adhesion, and the pathogenesis of human diseases such as Alzheimer's disease (AD). Recent studies from our laboratories have shown that agrin is a major extracellular matrix (ECM) and transmembrane HSPG in nervous tissue. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction (NMJ). Emerging evidence indicates that agrin's function is not limited to its role in synaptogenesis, as agrin modulates axon extension, is expressed in adult brain, and may contribute to the etiology of some neurodegenerative diseases. The studies outlined in this proposal are aimed at understanding mechanisms by which agrin functions in brain development and aging. The specific goals of this proposal are: 1) To analyze the role of agrin in neurogenesis, neural patterning and axonal growth in the developing CMS, using in vivo approaches in chicken and zebrafish embryos. These studies will focus on analyzing the role agrin plays in modulating the function of heparin-binding signaling molecules such as the fibroblast growth factors (FGFs). Agrin morpholino oligonucleotides will be employed to knock-down agrin expression during chick or zebrafish development, and will be combined with inhibitors of FGF receptor function or FGF overexpression to explore agrin's role in the modulation of FGF signaling during development. 2) To elucidate the molecular mechanisms by which agrin regulates posterior development in zebrafish. These studies will test the hypothesis that agrin, via regulation of FGF signaling pathways, is necessary for posterior development in zebrafish. 3) To examine the role of agrin in the regulation of beta-amyloid aggregation, clearance and cytotoxicity in AD brain. These studies represent a continuation of our studies that suggest a crucial role for agrin in modulating beta-amyloid aggregation. These studies will include the use of AD mouse models to investigate further the role of agrin in AD. We predict that these proposed studies will provide important new insight into the function of agrin in the developing and aging nervous system.
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