Abstract

Although amyloid β (Aβ) deposition has been a hallmark of Alzheimer’s disease (AD), the physiological function of amyloid precursor protein (APP) is not clear. Our results suggested that high concentration of APP induces glial differentiation while physiological level of APP promotes migration and differentiation of neural stem cell (HNSC). HNSCs were mainly differentiated into astrocytes when they are transplanted into APP transgenic mouse brain or treated with a high concentration of secreted-type APP (sAPP) in culture. Staurosporine (STS) induced a distinctive astrocytic morphology in NT-2/D1 neural progenitor cells with expressions of APP and astrocyte-specific markers, glial fibrillary acidic protein (GFAP), aspartate transporter, and glutamate transporter-1. Expression of APP is correlated with GFAP expression in both mRNA and protein level in this experiment. Inhibition of APP expression by RNA interference (RNAi) or treatment with MEK1 inhibitor (PD098059), which reduces APP expression by suppressing ERK phosphorylation, abolished GFAP expression. These results indicate that STS induces glial differentiation of neuronal progenitor cells by increasing APP levels through activation of ERK pathway. We also found that APP-induced glial differentiation of neural progenitor NT-2/D1 cells is mediated by activation of IL-6/gp130 and notch signaling pathway. Treatment of APP activated IL-6/gp130 signal pathway via protein-protein interaction between APP and gp130 and it increased the gene expressions of CNTF, gp130 and JAK1, and phosphorylation of STAT3 while gene silencing of CNTF, JAK1 or STAT3 by RNAi, or treatment the cells with antibodies recognizing gp130 suppressed GFAP expression, indicating these molecules are crucial for APP-induced glial differentiation. Thus treatment of sAPP may promote glial differentiation of neural progenitor cells by activation of IL-6/gp130 signaling cascade. Treatment of sAPP increased the generation of notch intracellular domain as well as gene expression of Hes1 but did not change expression levels of notch or its ligands. We also found protein-protein interaction of APP and notch using immunoprecipitation suggesting that glial differentiation of NT-2/D1 cells is mediated by the physical interaction between APP and notch. N-terminal domain of APP (1-205 a.a.) alone can bind to notch and activate these signaling cascade in NT-2/D1 cells. Thus, APP may induce glial differentiation through activation of IL-6/gp130 and notch signal cascade by binding with its N-terminal domain. Taken together, our results suggest that APP regulates neural stem cell (NSC) differentiation through IL-6/gp130 and notch signaling pathway. Furthermore, the activation of both glial differentiation mechanisms may be necessary to potentiate APP-induced glial differentiation of NSC. Altered APP metabolism in Down syndrome and Alzheimer’s disease may accelerate premature glial differentiation of NSCs, resulting in gliosis found in these diseases. Although it is not clear that how adult neurogenesis contributes to maintain normal brain function, destruction of neuroreplacement mechanism by NSCs may pose a problem. We may also have to consider effect of APP on the stem cell therapy for these diseases, since HNSCs may not properly differentiate into neurons under these pathological conditions.

Notes

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Graduation Date

2006

Semester

Fall

Advisor

Sugaya, Kiminobu

Degree

Doctor of Philosophy (Ph.D.)

College

Burnett College of Biomedical Sciences

Degree Program

Biomolecular Science

Format

application/pdf

Identifier

CFE0001375

URL

http://purl.fcla.edu/fcla/etd/CFE0001375

Language

English

Release Date

October 2018

Length of Campus-only Access

None

Access Status

Doctoral Dissertation (Open Access)

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