Apolipoprotein E evoked intracellular signaling: A mechanism of biologic activity.

摘要

The nervous system responds to injury and to neurodegenerative diseases with coordinated changes in expression of many proteins, including growth and survival factors, cell surface receptors and secreted extracellular proteins. The ability of the nervous system to recover from acute and chronic injury depends on proper functioning of these proteins. Expression of apolipoprotein E (apoE) is upregulated following injury to the central nervous system (CNS). ApoE occurs as 3 predominant isoforms in the human population and has isoform-specific effects on the course of recovery from a variety of CNS injuries, including stroke, intracerebral hemorrhage and closed head injury. The apoE4 isoform is also associated with higher risk and younger age of onset of Alzheimer's Disease. Despite a growing body of evidence showing the importance of apoE in recovery from injury, the cellular functions of apoE in the nervous system remain largely undefined. Undoubtedly, elucidating the cellular roles of apoE in the nervous system is important for understanding how this protein can effect the course of recovery after CNS injury. The goal of this dissertation was to gain insights into the cellular functions of apoE. Central to this goal is the identification of direct effects of apoE, as well as describing functional interactions that apoE has with other proteins. Toward that end, I present here evidence that lipid-free apoE, and peptides from the receptor-binding region of apoE, effect the survival and cellular function of neuronal cells. Specifically, apoE directly binds several growth factors, among them the injury-associated factor ciliary neurotrophic factor (CNTF). Furthermore, apoE potentiates the survival-promoting effects of CNTF on cultured hippocampal neurons, and apoE and mimetic peptides from the receptor-binding region elicit an intracellular signaling cascade that is mediated by mobilization of IP3, Ca 2+ and PKC. These data support my hypothesis that apoE functions in the nervous system with direct intracellular-signaling, possibly also by downstream interactions with pathways activated by growth factors and other signaling proteins.