Metabotropic Glutamate Receptors Modulate Exocytotic Tau Release and Propagation

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 383; no. 2; pp. 117 - 128
• Main Authors: Mazzo, Francesca, Butnaru, Ioana, Grubisha, Olivera, Ficulle, Elena, Sanger, Helen, Fitzgerald, Griffin, Pan, Feng, Pasqui, Francesca, Murray, Tracey, Monn, James, Li, Xia, Hutton, Michael, Bose, Suchira, Schiavo, Giampietro, Sher, Emanuele
• Format: Journal Article
• Language: English
• Published: United States 01-11-2022
• Subjects: Alzheimer Disease - drug therapy; Animals; Calcium - metabolism; Exocytosis; Humans; Mice; N-Ethylmaleimide-Sensitive Proteins - metabolism; N-Ethylmaleimide-Sensitive Proteins - pharmacology; Receptors, Metabotropic Glutamate - metabolism; SNARE Proteins - metabolism; SNARE Proteins - pharmacology; Synaptosomes - metabolism; tau Proteins - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.122.001307

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.