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HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer’s Disease Brain

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Abstract

The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer’s disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over-expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic Aβ42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by Aβ treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the β-amyloid protein.

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Acknowledgments

This study was funded in part by Consejeria de Sanidad, Generalitat Valenciana (AP-091/08) and the Instituto de Salud Carlos III (ISCIII), Fondo de Investigaciones Sanitaria (grants PS09/00684 and PI11/03026 for JSV and CP11/00067 and PI14/00566 to MSGA); cofinanced by Fondo Europeo de Desarrollo Regional), the Torsten Söderberg Foundation at the Royal Swedish Academy of Sciences, and under the aegis of the EU BIOMARKAPD-Joint Programming on Neurodegenerative Diseases (JPND) project; and through CIBERNED, ISCIII, Spain.

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Authors and Affiliations

  1. Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d’Alacant, Spain

    María-Salud García-Ayllón, Arancha Botella-López, Inmaculada Cuchillo-Ibañez & Javier Sáez-Valero

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Sant Joan d’Alacant, Spain

    María-Salud García-Ayllón, Arancha Botella-López, Inmaculada Cuchillo-Ibañez, Alberto Rábano, Jesús Ávila & Javier Sáez-Valero

  3. Unidad de Investigación, Hospital General Universitario de Elche, FISABIO, Elche, Spain

    María-Salud García-Ayllón

  4. Banco de Tejidos de la Fundación CIEN, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain

    Alberto Rábano

  5. Karolinska Institute-Alzheimer Disease Research center, Stockholm, Sweden

    Niels Andreasen

  6. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

    Kaj Blennow

  7. Centro de Biología Molecular “Severo Ochoa”, Universidad, Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid, Spain

    Jesús Ávila

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  1. María-Salud García-Ayllón
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Correspondence to María-Salud García-Ayllón or Javier Sáez-Valero.

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MSGA and JSV are inventors of a patent submitted for the application of HNK-1 as an AD biomarker.

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Supplemental Figure 1

Immunoreactive HNK-1 carrier glycoforms in human brain extracts. New fresh aliquots of the protein extracts (40 μg/lane) from non-demented controls (NDC, n = 10), and Alzheimer’s (AD, n = 12) frontal cortex (same samples analyzed in Fig. 1), were blotted with an alternative anti-HNK-1 antibody (mouse Ab-2 antibody). Western blot was performed following the same protocols of the previous blots that were probed with the clone VC1.1 antibody. A representative blot is shown. (TIF 358 kb)

Supplemental Figure 2

HNK-1 glycoproteins in brain and cellular extracts of P-tau over-expressing mice and cellular models. (A) Representative blots from brain extracts (cortices) of Tg-VLW (n = 6 analyzed) and non-transgenic animals (n = 6, NTg) were probed with an anti-HNK-1 antibody (clone VC1.1). *Longer exposure of the bottom of the same gel, an area which display less intense HNK-1 immunoreactivity. Whether modulating P-tau affected HNK-1 levels was also evaluated in SH-SY5Y cells over-expressing P-tau. (B) Hyperphosphorylation of tau in SH-SY5Y cells co-transfected with human tau and GSK3β. The levels of GSK3β, total-tau (T-tau), and P-tau are illustrated in representative examples of transfected (P-tau) and control cells (Cont; empty vector). (C) Immunodetection of HNK-1 in the same cells is also shown in a representative blot. Tubulin was used as a loading control and it was assessed in the same blots (bottom panels). There were no statistically significant differences between NDC and AD groups. (TIF 799 kb)

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García-Ayllón, MS., Botella-López, A., Cuchillo-Ibañez, I. et al. HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer’s Disease Brain. Mol Neurobiol 54, 188–199 (2017). https://doi.org/10.1007/s12035-015-9644-x

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