Trace amine associate receptor 1 (TAAR1) as a new target for the treatment of cognitive dysfunction in Alzheimer disease

• ¹ University of Mons, Belgium
• ² Istituto Italiano di Tecnologia, Italy
• ³ Saint Petersburg State University, Russia

Alzheimer disease (AD) is the main cause of dementia with approximately 27 million people affected worldwide. Beta-Amyloid peptide (Ab) is elevated in the brains of patients with AD and is believed to be causative in the disease process. Ab can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory [1]. LTP involves postsynaptic phosphorylation and glutamate receptor trafficking, particularly; it has been shown that amyloid can cause reduction of glutamatergic transmission and inhibition of synaptic plasticity via increased endocytosis of NMDA receptors. Trace Amines (TAs) are a family of endogenous compounds with strong structural similarity to the classical monoamine neurotransmitters. The molecular mechanism of the TAs involves binding to a novel G protein-coupled receptor, called TAAR (trace amine-associated receptor). TAAR1 is distributed in the CNS. Recently, it has been shown that selective activation of TAAR1 are able to reverse glutamatergic hypofunction induced by selective NMDA receptor antagonists suggesting that TAAR1 activation may enhance also glutamatergic function. There are several lines of evidence suggesting pro-cognitive action of TAAR1 agonists in various behavioral experimental protocols and there is evidence indicating that TAAR1 can modulate frontal cortex glutamate NMDA receptor– related functions. [2-5]. Objectives: 1. To study in vitro the role of TAAR1 agonists on basal cortical glutamatergic transmission and their beneficial effect on Ab-induced dysfunction. 2. To study, in vivo, the role of TAAR1 in cognitive dysfunction induced by Ab and the beneficial role of TAAR1 agonists on cognition in Alzheimer’s mouse models. Methods: In vitro experiments were conducted on primary cortical cultures. Cortices of E17 embryo from TAAR1 and control mice were isolated and incubated for 14 days at 37 °C and 5% CO2. Cells were then stimulated with Ab 1-42 (1 µM, AnaSpec, USA), TAAR1 agonist (RO5256390, Sigma Aldrich, Belgium, 1 µM) or both 1hr at 37°C and NMDA surface expression was assessed using biotinylation assay and Western blots. In vivo studies were performed using 10-weeks mice ICV injected with: Ab 1-42 (3 µl), TAAR1 agonist (3µl) or both and vehicle treated controls. 7 days later, a series of behavioral tests were performed to evaluate the effects of Ab 1-42 and TAAR1 agonist, including Morris Water Maze (MWM), novel object recognition (NOR) and open field. Results: In vitro data showed that, as expected in WT mice, Ab 1-42 significantly decreased NMDA surface (NR1: -35± 2.6%; NR2A: -38± 1.8%; NR2B: -47± 4.2% ) expression while TAAR1 agonist promotes their membrane localization (NR1: +48±4.8%; NR2A: +67±3.5%; NR2B: +52±3.8% p<0.05, Student t test) on cortical cells. Conclusion: Altogether, our results showed that in vitro, TAAR1 agonist displayed the ability of increasing NMDA receptors surface expression, suggesting the possibility of displaying therapeutic effect on cognitive Ab induced impairments. Whether these effects are reproducible in vivo, are currently addressed.