DNA polymerase-β mediates the neurogenic effect of β-amyloid protein in cultured subventricular zone neurospheres.

Abstract:

β-Amyloid protein (Aβ) is thought to be responsible for neuronal apoptosis in Alzheimer's disease (AD). Paradoxically, Aβ can also promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells (NPCs) to differentiate into neurons. However, the mechanisms of Aβ-induced neurogenesis are unknown. Here we examined the role of DNA polymerase-β (DNA pol-β), a DNA repair enzyme that is required for proper neurogenesis during brain development and is also responsible for Aβ-induced neuronal apoptosis. In neurospheres obtained from the adult mouse subventricular zone (SVZ), the knockdown of DNA pol-β 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 Aβ(42) , the expression levels of DNA pol-β were rapidly increased. DNA pol-β knockdown prevented the Aβ(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-β prevented Aβ(42) -induced differentiation of progenitors into MAP-2(+) neurons. Thus, our data demonstrate that Aβ(42) arrests the proliferation of a subpopulation of nestin(+) cells via the induction of DNA pol-β, thereby allowing for their differentiation toward the neuronal lineage. Our findings reveal a novel role of DNA pol-β in Aβ(42) -induced neurogenesis and identify DNA pol-β as a key mechanistic link between the neurogenic effect of Aβ(42) on NPCs and the proapoptotic effect of Aβ(42) on mature neurons.

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Topics:

Health/Disease

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