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Potential Mechanism of Cellular Uptake of the Excitotoxin Quinolinic Acid in Primary Human Neurons

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Abstract

In Alzheimer’s disease (AD), excessive amounts of quinolinic acid (QUIN) accumulate within the brain parenchyma and dystrophic neurons. QUIN also regulates glutamate uptake into neurons, which may be due to modulation of Na+-dependent excitatory amino acid transporters (EAATs). To determine the biological relationships between QUIN and glutamate dysfunction, we first quantified the functionality and kinetics of [3H]QUIN uptake in primary human neurons using liquid scintillation. We then measured changes in the protein expression of the glutamate transporter EAAT3 and EAAT1b in primary neurons treated with QUIN and the EAAT inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid (2,4-PDC) using western blotting and immunohistochemistry. Immunohistochemistry was further used to elucidate intracellular transport of exogenous QUIN and the lysosomal-associated membrane protein 2 (LAMP2). Structural insights into the binding between QUIN and EAAT3 were further investigated using molecular docking techniques. We report significant temperature-dependent high-affinity transport leading to neuronal uptake of [3H]QUIN with a Km of 42.2 μM, and a Vmax of 9.492 pmol/2 min/mg protein, comparable with the uptake of glutamate. We also found that QUIN increases expression of the EAAT3 monomer while decreasing the functional trimer. QUIN uptake into primary neurons was shown to involve EAAT3 as uptake was significantly attenuated following EAAT inhibition. We also demonstrated that QUIN increases the expression of aberrant EAAT1b protein in neurons further implicating QUIN-induced glutamate dysfunction. Furthermore, we demonstrated that QUIN is metabolised exclusively in lysosomes. The involvement of EAAT3 as a modulator for QUIN uptake was further confirmed using molecular docking. This study is the first to characterise a mechanism for QUIN uptake into primary human neurons involving EAAT3, opening potential targets to attenuate QUIN-induced excitotoxicity in neuroinflammatory diseases.

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Abbreviations

[3H]QUIN:

3H Quinolinic acid

DAPI:

4′,6-Diamidino-2-phenylindole dihydrochloride

ATP:

Adenosine triphosphate

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

ALS:

Amyotrophic lateral sclerosis

Asp:

Aspartate

CSF:

Cerebrospinal fluid

MK-801:

Dizocilpine hydrogen maleate

ER:

Endoplasmic reticulum

EAAT:

Excitatory amino acid transporter

FBS:

Foetal bovine serum

GFAP:

Glial fibrillary acidic protein

Glu:

Glutamate

HBBS:

Hank’s balanced salt solution

HD:

Huntington’s disease

HCl:

Hydrochloric acid

IDO-1:

Indoleamine 2,3 dioxygenase

IFN-γ:

Interferon gamma

KP:

Kynurenine pathway

2,4-PDC:

l-trans-pyrrolidine-2,4-dicarboxylic acid

MAP 2:

Microtubule assembly protein 2

NMDA-R:

N-methyl d-aspartate receptor

NAD+ :

Nicotinamide adenine dinucleotide

NO:

Nitric oxide

NGS:

Normal goat’s serum

PBS:

Phosphate-buffered saline

PKC:

Protein kinase C

QPRTase:

Quinolinate phosphoribosyl transferase

QUIN:

Quinolinic acid

NaOH:

Sodium hydroxide

TRP:

Tryptophan

TNF-α:

Tumour necrosis factor alpha

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Acknowledgements

The authors acknowledge the Curran Foundation (Australia) and the Rebecca Cooper foundation (Australia) for their philanthropic support.

Availability of Data and Materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding

This work has also been supported by the National Health and Medical Research Council (APP1128849). Dr. Nady Braidy is the recipient of an Australian Research Council Discovery Early Career Research Award (DE170100628) at the University of New South Wales.

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Author notes

  1. Nady Braidy and Hayden Alicajic contributed equally to this work.

Authors and Affiliations

  1. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nady Braidy

  2. School of Medicine, Huzhou University, Wuxing District, Huzhou, Zhejiang, China

    Nady Braidy

  3. Neuropharmacology group, MND and Neurodegenerative diseases Research Centre, Macquarie University, Sydney, NSW, 2019, Australia

    Hayden Alicajic & Gilles J. Guillemin

  4. University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia

    David Pow

  5. Department of Chemistry and Biomolecular sciences, Macquarie University, Sydney, NSW, Australia

    Jason Smith

  6. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia

    Bat-Erdene Jugder

  7. St Vincent’s Centre for Applied Medical Research, Sydney, Australia

    Bruce J. Brew

  8. Department of Neurology and HIV Medicine, St Vincent’s Hospital, Sydney, Australia

    Bruce J. Brew

  9. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

    Joseph A. Nicolazzo

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  1. Nady Braidy
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  8. Gilles J. Guillemin
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Contributions

NB and HA performed the cell culture and molecular biology experiments. Molecular modelling was performed by JS. Experimental work was supervised by DP, JAN, GJG, and BJB. Figure 7 was drawn by B-EJ. All authors contributed to writing the manuscript.

Corresponding authors

Correspondence to Nady Braidy or Gilles J. Guillemin.

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Ethics Approval and Consent to Participate

All authors confirm that all experiments were performed in accordance with relevant guidelines and regulations. Human foetal tissue was obtained following informed written consent. This has been approved by the Human Ethics Committees from the University of New South Wales (UNSW Ethic approval HREC 03187) and the Macquarie University HREC committee.

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The authors declare that they have no competing interests.

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Braidy, N., Alicajic, H., Pow, D. et al. Potential Mechanism of Cellular Uptake of the Excitotoxin Quinolinic Acid in Primary Human Neurons. Mol Neurobiol 58, 34–54 (2021). https://doi.org/10.1007/s12035-020-02046-6

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