1. Targeting neural precursors in the adult brain rescues injured dopamine neurons.
- Author
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Androutsellis-Theotokis A, Rueger MA, Park DM, Mkhikian H, Korb E, Poser SW, Walbridge S, Munasinghe J, Koretsky AP, Lonser RR, and McKay RD
- Subjects
- Angiogenesis Inducing Agents pharmacology, Angiogenesis Inhibitors pharmacology, Animals, Blood Vessels drug effects, Blood Vessels metabolism, Brain drug effects, Brain metabolism, Cell Death drug effects, Cytoprotection drug effects, Neurons drug effects, Neurons metabolism, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 metabolism, Stem Cells drug effects, Stem Cells metabolism, Brain pathology, Dopamine metabolism, Neurons pathology, Stem Cells cytology
- Abstract
In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis.
- Published
- 2009
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