Kainate Receptor Activation Enhances Amyloidogenic Processing of APP in Astrocytes

Abstract

Kainic acid (KA) is an analogue of the excitatory neurotransmitter glutamate that, when injected systemically into adult rats, can trigger seizures and progressive neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy. However, biomolecular mechanisms responsible for the neuronal loss that occurs as a consequence of this treatment remains elusive. We have recently reported that toxicity induced by KA can partly be mediated by astrocyte-derived amyloid β (Aβ) peptides, which are critical in the development of Alzheimer’s disease (AD). Nonetheless, little is known how KA can influence amyloid precursor protein (APP) levels and processing in astrocytes. Thus, in the present study using human U-373 astrocytoma and rat primary astrocytes, we evaluated the role of KA on APP metabolism. Our results revealed that KA treatment increased the levels of APP and its cleaved products (α-/β-CTFs) in cultured U-373 astrocytoma and primary astrocytes, without altering the cell viability. The cellular and secretory levels of Aβ1–40/Aβ1–42 were markedly increased in KA-treated astrocytes. We also demonstrated that the steady-state levels of APP-secretases were not altered but the activity of γ-secretase is enhanced in KA-treated U-373 astrocytoma. Furthermore, using selective receptor antagonists, we showed that the effects of KA is mediated by activation of kainate receptors and not NMDA or AMPA receptors. These results suggest that KA can enhance amyloidogenic processing of APP by activating its own receptor leading to increased production/secretion of Aβ-related peptides from activated astrocytes which may contribute to the pathogenesis of temporal lobe epilepsy.

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Acknowledgements

This work is supported by a grant from the Canadian Institutes of Health Research (CIHR) to S.K. D.O. is a recipient of a studentship award from the Natural Sciences and Engineering Research Council (NSERC) of Canada. We would like to indicate that none of the authors included in this manuscript has had any actual or potential conflict of interest including financial, personal, or other relationships with other people or organizations at any time that could inappropriately influence the work.

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D.O. and A.S. performed experiments, analyzed data, and wrote the manuscript. S.K. conceived the study, analyzed data, and wrote the manuscript.

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Correspondence to Satyabrata Kar.

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Electronic supplementary material

Supplementary Fig. 1
figure8

Immunoblots and corresponding histograms showing time-dependent effects of 100 μM kainic acid (KA) on the levels of components of γ-secretase complex nicastrin (A), APH1 (B), and PEN2 (C) in cultured U-373 cells. Note that KA treatment did not alter the steady-state levels of either nicastrin, PEN2, or APH1 in cultured U-373 cells. All Western blots were re-probed with β-actin antibody to monitor protein loading. Data represent means ± SEM from three to four independent experiments. Cont, control; KA, kainic acid. (PNG 121 kb)

Supplementary Fig. 2
figure9

A–I: Representative confocal images showing cellular distribution of immunoreactive NMDA receptor (NMDAR) and GFAP (A–C), AMPA receptor (AMPAR) and GFAP (D–F), and kainate receptor (KR) and GFAP (G–I) in control cultured U-373 cells. Note the cellular distribution of three types of ionotropic glutamatergic receptors in GFAP-positive U-373 cells. Identity of primary antibodies is indicated by respective font colors. Scale = 20 μm. (PNG 1376 kb)

Supplementary Fig. 3
figure10

Immunoblots and corresponding histograms showing time-dependent effects of 100 μM kainic acid (KA) on the levels of β-secretase BACE1 (A) and components of γ-secretase complex PS1 (A) in cultured rat primary hippocampal astrocytes. Note that KA treatment did not alter the steady-state levels of either BACE1 or PS1 in rat astrocytes. All Western blots were re-probed with β-actin antibody to monitor protein loading. Data represent means ± SEM from three to four independent experiments. Cont, control; KA, kainic acid. (PNG 87 kb)

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Ourdev, D., Schmaus, A. & Kar, S. Kainate Receptor Activation Enhances Amyloidogenic Processing of APP in Astrocytes. Mol Neurobiol 56, 5095–5110 (2019). https://doi.org/10.1007/s12035-018-1427-8

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Keywords

  • Amyloid precursor protein
  • β-Amyloid
  • Epilepsy
  • Glial cells
  • Kainic acid