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Metabotropic Glutamate Receptors Modulate Exocytotic Tau Release and Propagation

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posted on 2023-01-10, 10:57 authored by Francesca Mazzo, Ioana Butnaru, Olivera Grubisha, Elena Ficulle, Helen Sanger, Griffin Fitzgerald, Feng Pan, Francesca Pasqui, Tracey Murray, James Monn, Xia Li, Michael Hutton, Suchira Bose, Giampietro Schiavo, Emanuele Sher

Using synaptosomes purified from the brains of two transgenic mouse models overexpressing mutated human tau (TgP301S and Tg4510) and brains of patients with sporadic Alzheimer’s disease, we showed that aggregated and hyperphosphorylated tau was both present in purified synaptosomes and released in a calcium- and synaptosome-associated protein of 25 kDa (SNAP25)-dependent manner. In all mouse and human synaptosomal preparations, tau release was inhibited by the selective metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495. LY379268 was also able to block pathologic tau propagation between primary neurons in an in vitro microfluidic cellular model. These novel results are transformational for our understanding of the molecular mechanisms mediating tau release and propagation at synaptic terminals in Alzheimer’s disease and suggest that these processes could be inhibited therapeutically by the selective activation of presynaptic G protein–coupled receptors.


SIGNIFICANCE STATEMENT Pathological tau release and propagation are key neuropathological events underlying cognitive decline in Alzheimer’s disease patients. This paper describes the role of regulated exocytosis, and the soluble N-ethylmaleimide–sensitive factor attachment receptor (SNARE) protein SNAP25, in mediating tau release from rodent and human synaptosomes. This paper also shows that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.

History

Author affiliation

School of Psychology and Vision Sciences, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

The Journal of Pharmacology and Experimental Therapeutics

Volume

383

Issue

2

Pagination

117 - 128

Publisher

American Society for Pharmacology and Experimental Therapeutics (ASPET)

issn

0022-3565

eissn

1521-0103

Copyright date

2022

Available date

2023-01-10

Language

English

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