Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 90, Issue 3, Pages 559-567Publisher
WILEY-BLACKWELL
DOI: 10.1002/jnr.22780
Keywords
DNA polymerase-ss; ss-amyloid; neurogenesis; neurosphere; neural stem cell; Alzheimer's disease
Categories
Funding
- National Institutes of Health [R01NS061983, R01ES015988]
- National Multiple Sclerosis Society
- Shriners Hospitals for Children
- Italian Ministry of University and Research [105/04]
Ask authors/readers for more resources
beta-Amyloid protein (A beta) is thought to be responsible for neuronal apoptosis in Alzheimer's disease (AD). Paradoxically, A beta can also promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells (NPCs) to differentiate into neurons. However, the mechanisms of A beta-induced neurogenesis are unknown. Here we examined the role of DNA polymerase-beta (DNA pol-beta), a DNA repair enzyme that is required for proper neurogenesis during brain development and is also responsible for A beta-induced neuronal apoptosis. In neurospheres obtained from the adult mouse subventricular zone (SVZ), the knockdown of DNA pol-beta or its pharmacological blockade showed that the enzyme functioned both to repress proliferation of early nestin+ progenitor cells and to promote the maturation of TuJ-1+ neuronal cells. In neurospheres challenged with oligomers of synthetic A beta 42, the expression levels of DNA pol-beta were rapidly increased. DNA pol-beta knockdown prevented the A beta 42-promoted differentiation of nestin+ progenitor cells into nestin+/Dlx-2+ neuroblasts. Moreover, when neurospheres were seeded to allow full differentiation of their elements, blockade of DNA pol-beta prevented A beta 42-induced differentiation of progenitors into MAP-2+ neurons. Thus, our data demonstrate that A beta 42 arrests the proliferation of a subpopulation of nestin+ cells via the induction of DNA pol-beta, thereby allowing for their differentiation toward the neuronal lineage. Our findings reveal a novel role of DNA pol-beta in A beta 42-induced neurogenesis and identify DNA pol-beta as a key mechanistic link between the neurogenic effect of A beta 42 on NPCs and the proapoptotic effect of A beta 42 on mature neurons. (c) 2011 Wiley Periodicals, Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available