[en] Worldwide, approximately 27 million people are affected by Alzheimer's disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1-42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD.
Targa, Giorgia ; UNIMI - Università degli Studi di Milano [IT]
Espinoza, Stefano ; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), 16163 Genova, Italy
Villers, Agnès ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Neurosciences
Gainetdinov, Raul R; Institute of Translational Biomedicine, St. Petersburg State University, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia ; St. Petersburg University Hospital, St. Petersburg State University, Universitetskaya Emb. 7-9, 199034 St. Petersburg, Russia
Ris, Laurence ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Neurosciences
Language :
English
Title :
Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease.
R550 - Institut des Sciences et Technologies de la Santé R100 - Institut des Biosciences
Funders :
Russian Science Foundation Stichting Alzheimer Onderzoek (SAO)- Fondation Recherche Alzheimer (FRA), SAO-FRA grant programme.
Funding text :
This study was financially supported by Stichting Alzheimer Onderzoek (SAO)-Fondation Recherche Alzheimer (FRA), SAO-FRA grant programme. R.R.G. is supported by the Russian Science Foundation grant 19-75-30008.
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