Amyloid Precursor Protein Regulates Differentiation of Human Neural Stem Cells

Abstract

Although amyloid beta (Abeta) deposition has been a hallmark of Alzheimer's disease (AD), the absence of a phenotype in the beta amyloid precursor protein (APP) knockout mouse, tends to detract our attention away from the physiological functions of APP. Although much attention has been focused on the neurotoxicity of Abeta, many studies suggest the involvement of APP in neuroplasticity. We found that secreted amyloid precursor protein (sAPP) increased the differentiation of human neural stem cells (hNSCs) in vitro, while an antibody-recognizing APP dose-dependently inhibited these activities. With a high dose of sAPP treatment or wild-type APP gene transfection, hNSCs were differentiated into astrocytes rather than neurons. In vivo, hNSCs transplanted into APP-transgenic mouse brain exhibited glial differentiation rather than neural differentiation. Our results suggest that APP regulates neural stem cell biology in the adult brain, and that altered APP metabolism in Down syndrome or AD may have implications for the pathophysiology of these diseases.

Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine

“…In a recent study, we demonstrated that treatment with recombinant sAPP promoted migration and differentiation of HNSCs in culture, and 22C11 antibodymediated neutralization of sAPP in media inhibited these effects dose dependently (15). We also reported that HNSCs transplanted into APP knockout mice showed less migration and differentiation compared with wild-type mice (15). On the basis of these observations, we suggest that APP may be acting as a signaling factor in migration and differentiation of HNSCs.…”

“…Both of these events involve migration and differentiation of NSCs, suggesting that APP may also play an important physiological function in regulating stem cell biology. In a recent study, we demonstrated that treatment with recombinant sAPP promoted migration and differentiation of HNSCs in culture, and 22C11 antibodymediated neutralization of sAPP in media inhibited these effects dose dependently (15). We also reported that HNSCs transplanted into APP knockout mice showed less migration and differentiation compared with wild-type mice (15).…”

“…This study demonstrated that the aged rat brain was capable of providing necessary environmental conditions for HNSCs to retain their multipotency and provided some evidence for the potential of stem cell replacement therapies to improve memory and cognitive deficits in AD. However, we recently found increased in vitro glial differentiation of HNSCs treated with high doses of secreted APP or transfected with wild-type APP (15). This finding suggests that stem cell replacement approaches would have reduced effectiveness in the AD brain, in which impaired APP metabolism would prevent or reduce neuronal differentiation of implanted cells.…”

Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

“…A large number of studies have suggested that sAPP␣ has trophic properties on neural stem cells (9,27,28,37,38). In our studies, recombinant human sAPP␣ had no effect on proliferation, nor did immunoprecipitation of endogenous secreted mouse sAPP␣ inhibit proliferation.…”

Alzheimer's Disease Affects Progenitor Cells through Aberrant β-Catenin Signaling

“…It was previously shown that human NPCs exposed to high concentrations of secreted APP differentiated into astrocytes rather than into neurons. In vivo, human NPCs transplanted into the brain of APP transgenic mice preferentially differentiated into glia (Kwak et al, 2006), indicating that under physiological conditions APP plays a role in neural stem biology, probably by inducing STAT3 phosphorylation and JAK1 gene expression (Sugaya, 2008). APP was also shown to increase generation of Notch intracellular domain and expression of Hes1, a mechanism which may work in concert with the JAK/STAT pathway to push differentiation of human NPCs toward glia (Sugaya, 2008).…”