Soluble APP functions as a vascular niche signal that controls adult neural stem cell number

Abstract

The molecular mechanism by which NSC number is controlled in the neurogenic regions of the adult brain is not fully understood but it has been shown that vascular niche signals regulate neural stem cell (NSC) quiescence and growth. Here, we have uncovered a role for soluble amyloid precursor protein (sAPP) as a vascular niche signal in the subventricular zone (SVZ) of the lateral ventricle of the adult mouse brain. sAPP suppresses NSC growth in culture. Further in vivo studies on the role of APP in regulating NSC number in the SVZ clearly demonstrate that endothelial deletion of App causes a significant increase in the number of BrdU label-retaining NSCs in the SVZ, whereas NSC/astrocyte deletion of App has no detectable effect on the NSC number. Taken together, these results suggest that endothelial APP functions as a vascular niche signal that negatively regulates NSC growth to control the NSC number in the SVZ.

Endothelial cells maintain neural stem cells quiescent in their niche

“…Nevertheless, deciphering the complex mechanisms involved in this process may be very challenging in the brain. In a recent article in Development , Sato and colleagues revealed an important component of the neural stem cell (NSC) niche: an endothelial cell-derived molecule that keeps NSCs’ quiescence in the subventricular zone in vivo (Sato et al, 2017). The authors identified by in vitro assays soluble amyloid precursor protein (APP) as an extrinsic cue that suppresses NSCs’ growth, and enhances neurosphereforming ability, while retaining their multipotency.…”

“…Furthermore, Sato and colleagues investigated the role of APPs on NSCs in vivo by using APP-null mouse model. The authors discovered that, in the absence of APP, NSCs’ proliferation in the subventricular zone increases, suggesting that APP is important for NSCs’ quiescence in their niche (Sato et al, 2017). …”

“…These experiments revealed that endothelial cells, but not astrocytes, regulate NSCs’ proliferation in the subventricular zone via APP (Sato et al, 2017). This study uncovers an important molecular component of the NSC microenvironment: APP derived from endothelial cells.…”

“…The main findings from this study are based on the data obtained from Tie2-Cre/APP-floxed mice (Sato et al, 2017). It is known that Tie2-Cre mice exhibit Cre recombinase activity in both hematopoietic and endothelial cells (Tang et al, 2010).…”

“…The functional heterogeneity of NSCs points to the potential for matching heterogeneity in the microenvironmental influences that support the function and behavior of these NSC subsets. Sato and colleagues analyzed the subventricular zone NSCs as one whole population (Sato et al, 2017). Nonetheless, it will be interesting in future experiments to distinguish the various NSC subsets, and determine whether they respond differently to APP.…”