The paper by Breunig et al. represents an elegant set of experiments, performed by a talented young investigator and aimed at dissecting the molecular mechanisms responsible for postnatal neurogenesis. Using tamoxofen-inducible Notch1 knockout mice and inducible Notch intracellular domain (NICD) transgenic mice, the authors show that Notch acts as a molecular “cell fate trigger” for determining the proliferation versus differentiation decision. Specifically, loss of Notch1 caused progenitors to exit the cell cycle while conversely, overexpression of the constitutively active NICD domain caused a striking three- to fourfold increase in proliferating cells in the dentate gyrus and subgranular zone. Importantly, the investigators validated their findings in this system by taking a pharmacological approach, where they used γ-secretase inhibition to recapitulate the effects observed in the inducible Notch1 knockout mice.

These findings have relevance for Alzheimer disease (AD) at a number of levels. The guiding principle for γ-secretase inhibition as an AD therapeutic approach...  Read more

The paper by Breunig et al. represents an elegant set of experiments, performed by a talented young investigator and aimed at dissecting the molecular mechanisms responsible for postnatal neurogenesis. Using tamoxofen-inducible Notch1 knockout mice and inducible Notch intracellular domain (NICD) transgenic mice, the authors show that Notch acts as a molecular “cell fate trigger” for determining the proliferation versus differentiation decision. Specifically, loss of Notch1 caused progenitors to exit the cell cycle while conversely, overexpression of the constitutively active NICD domain caused a striking three- to fourfold increase in proliferating cells in the dentate gyrus and subgranular zone. Importantly, the investigators validated their findings in this system by taking a pharmacological approach, where they used γ-secretase inhibition to recapitulate the effects observed in the inducible Notch1 knockout mice.

These findings have relevance for Alzheimer disease (AD) at a number of levels. The guiding principle for γ-secretase inhibition as an AD therapeutic approach has been the amyloid cascade hypothesis, which in its simplest form puts forth that cerebral amyloidosis produces a series of pathological downstream events that perpetrate AD. However, the results of Breunig et al. lead us to question whether such a therapeutic avenue will, in principle, be beneficial. This is because reducing amyloidosis by γ-secretase inhibition may come at the cost of shutting down adult neurogenesis occurring in the brains of AD patients. That is, of course, assuming that adult neurogenesis is even beneficial for reducing AD severity, a premise that remains questionable.

These results also cause us to critically consider the intersection between Notch and amyloid precursor protein (APP), which, as the above editorial rightly points out, both have γ-secretase cleavage in common. Does γ-secretase indiscriminately cleave both molecules, or does it perhaps give “preferential treatment” to one or the other? The latter has been suggested by the work of Paul Greengard’s group, who have shown that Gleevec is able to reduce APP cleavage/Aβ generation while leaving Notch cleavage unperturbed (Netzer et al., 2003). An answer to this question may allow for a more tailored AD therapeutic strategy aimed at reducing cerebral amyloidosis without the potentially unwanted side effect of shutting down adult neurogenesis.

References:
Breunig JJ, Silbereis J, Vaccarino FM, Sestan N, Rakic P. Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20558-63. Abstract

Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12444-9. Abstract

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