The axon's growing tip, the nerve growth cone advances by amoeboid locomotion, a process that involves concerted regulation of the actin cytoskeleton and cell adhesion. Growth cone adhesion is not well understood, but recent data indicate that amyloid precursor protein (APP) is enriched in growth cones and associated with their adhesions. This project will test the hypotheses that APP is involved in the regulation of integrin-mediated growth cone adhesion, and that APP affects growth cone motility in vitro and in vivo.
The specific aims are to test these hypotheses by: (1) analyzing growth cone spreading and adhesion in conditions of APP and integrin gain and loss of function in vitro;and (2) studying axonal growth and sprouting in vivo, in mutant mice mis-expressing APP.
These aims will be pursued with a combination of cell imaging, molecular and biochemical approaches as well as genetically engineered mouse models. The proposed studies are expected to provide new data on the growth cone's adhesion mechanism and, thus, are important for our understanding of axonal growth and pathfinding in development. Furthermore, results are expected to yield insights into the so far little understood function of APP, especially during nervous system development. As APP is over-expressed in Down syndrome, the expected data are likely to provide new insights into possible causes of cognitive deficits in Down syndrome children, and they also will impact our understanding of pathogenic processes in Alzheimer's disease.
During nervous system development, remodeling of connectivity, and regeneration after injury, growing nerve fibers are tipped by an amoeboid structure, the nerve growth cone. The proposed studies will investigate the poorly understood adhesive mechanism that is necessary for amoeboid motility. Recent results strongly implicate amyloid precursor protein (APP), a key player in the pathogenesis of Alzheimer's disease, in growth cone adhesion and motility. Interestingly, Down syndrome individuals overproduce APP in their brains, which raises the question of whether excess APP is involved in cognitive disability associated with Down syndrome. The focus of the proposed research is the role APP plays in growth cone adhesion and, thus, in the processes that enable nerve fibers to reach their targets in the brain. We expect that these studies will make significant contributions to our understanding of the function of APP in the developing and mature brain. Thus, the proposed research is highly relevant to the disease mechanisms leading to Down syndrome and Alzheimer's disease.
| Sosa, Lucas J; Postma, Nienke L; Estrada-Bernal, Adriana et al. (2014) Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome. FASEB J 28:195-205 |
| Sosa, Lucas J; Bergman, Jared; Estrada-Bernal, Adriana et al. (2013) Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance. PLoS One 8:e64521 |
| Estrada-Bernal, Adriana; Sanford, Staci D; Sosa, Lucas J et al. (2012) Functional complexity of the axonal growth cone: a proteomic analysis. PLoS One 7:e31858 |
| Sanford, Staci D; Yun, Bo Goen; Leslie, Christina C et al. (2012) Group IVA phospholipase Aýýý is necessary for growth cone repulsion and collapse. J Neurochem 120:974-84 |
