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Amyloid β-Peptide 1–42 Modulates the Proliferation of Mouse Neural Stem Cells: Upregulation of Fucosyltransferase IX and Notch Signaling

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Abstract

Amyloid β-peptides (Aβs) aggregate to form amyloid plaques, also known as senile plaques, which are a major pathological hallmark of Alzheimer’s disease (AD). Aβs are reported to possess proliferation effects on neural stem cells (NSCs); however, this effect remains controversial. Thus, clarification of their physiological function is an important topic. We have systematically evaluated the effects of several putative bioactive Aβs (Aβ1–40, Aβ1–42, and Aβ25–35) on NSC proliferation. Treatment of NSCs with Aβ1–42 significantly increased the number of those cells (149 ± 10 %). This was not observed with Aβ1–40 which did not have any effects on the proliferative property of NSC. Aβ25–35, on the other hand, exhibited inhibitory effects on cellular proliferation. Since cell surface glycoconjugates, such as glycolipids, glycoproteins, and proteoglycans, are known to be important for maintaining cell fate determination, including cellular proliferation, in NSCs and they undergo dramatic changes during differentiation, we examined the effect of Aβs on a number of key glycoconjugate metabolizing enzymes. Significantly, we found for the first time that Aβ1–42 altered the expression of several key glycosyltransferases and glycosidases, including fucosyltransferase IX (FUT9), sialyltransferase III (ST-III), glucosylceramide ceramidase (GLCC), and mitochondrial sialidase (Neu4). FUT9 is a key enzyme for the synthesis of the Lewis X carbohydrate epitope, which is known to be expressed in stem cells. Aβ1–42 also stimulated the Notch1 intracellular domain (NICD) by upregulation of the expression of Musashi-1 and the paired box protein, Pax6. Thus, Aβ1–42 upregulates NSC proliferation by modulating the expression of several glycogenes involved in Notch signaling.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid β-protein

FUT9:

Fucosyltransferase IX

NSC:

Neural stem cell

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Ganglioside:

Recommendations (1976) IUPAC-IUB Commission on Biochemical Nomenclature (1977) The nomenclature of lipids. Lipids 12(6):455–468 and according to Svennerholm L (1963) Chromatographic separation of human brain gangliosides. J Neurochem 10:613–623

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Acknowledgments

This work was supported in part by a VA Merit Review Award (1 IO1BX001388 to RKY) and NIH grants (RO1 NS26994 and RO1 NS11853 to RKY).

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The authors declare no conflict of interest.

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  1. Institute of Molecular Medicine and Genetics and Institute of Neuroscience, Medical College of Georgia, Georgia Regents University, Augusta, GA, 30912, USA

    Yutaka Itokazu & Robert K. Yu

  2. Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA

    Yutaka Itokazu & Robert K. Yu

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Correspondence to Robert K. Yu.

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Itokazu, Y., Yu, R.K. Amyloid β-Peptide 1–42 Modulates the Proliferation of Mouse Neural Stem Cells: Upregulation of Fucosyltransferase IX and Notch Signaling. Mol Neurobiol 50, 186–196 (2014). https://doi.org/10.1007/s12035-014-8634-8

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