A2A adenosine receptor deletion is protective in a mouse model of Tauopathy

Abstract

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

“…Thus, specific A 2A R antagonists may represent a novel pharmacological strategy for controlling neurodegeneration in synucleinopathy. This neuroprotection against neurodegeneration in synucleinopathy is also in agreement with a broader spectrum of neuroprotection by A 2A R inactivation in the brain (Chen et al, 2007;Gomes et al, 2011), including animal models of ischemia (Chen et al, 1999), PD (Carta et al, 2009;Chen et al, 2001;Ikeda et al, 2002;Kachroo and Schwarzschild, 2012), AD (Canas et al, 2009b;Dall'Igna et al, 2007), tauopathy (Laurent et al, 2016), amyotrophic lateral sclerosis (Ng et al, 2015), Machado-Joseph disease (Goncalves et al, 2013), and traumatic brain injury (Dai et al, 2010).…”

“…A 2A R deletion may protect against α-Syn aggregation and neurodegeneration by decreasing the phosphorylation of α-Syn on Ser129. The notion that A 2A R may modulate phosphorylation modifications of pathological proteins collaborates with the recent finding that A 2A R antagonist MSX-3 significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice (Laurent et al, 2016). Alternatively, A 2A R deletion may prevent α-Syn aggregation by control of ubiquitin-proteasome system (UPS) and autolysosome activity associated with degradation of the accumulated α-Syn (Cuervo et al, 2004;Webb et al, 2003).…”

“…PD patients show a noted safety profile (Chen et al, 2013). Further investigation into interplay between G protein-coupled receptors and pathological accumulated proteins, including Aβ (Canas et al, 2009b;Dall'Igna et al, 2007;Orr et al, 2015), α-Syn (Ferreira et al, 2015), Tau (Laurent et al, 2016) and ataxin-3 (Goncalves et al, 2013), may offer new therapeutic opportunities for controlling protein aggregation, neurodegeneration and cognitive impairments. WT and A 2A R KO mice were bilaterally injected with PBS or A53T α-Syn fibrils into DG and analyzed for working memory and locomotor activity at two months after the injection.…”

Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy

“…In the present study, we sought to investigate the relationships between tau pathology and brain innate and cellular adaptive immunity using the THY-Tau22 mouse model, which progressively develops hippocampal tauopathy and spatial memory deficits (Burnouf et al , 2013; Laurent et al , 2016). In addition to the expected activation of microglia and astrocytes, our data demonstrate that hippocampal tau pathology is associated with chemokine production and parenchymal T cell infiltration.…”

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…The importance of this modulation system is best heralded by the observation that the overactivation of hippocampal A 2A Rs is necessary and sufficient to trigger spatial memory dysfunction (Li et al, 2015a;Pagnussat et al, 2015). Furthermore, conditions associated with memory deterioration trigger an upregulation of A 2A Rs in the hippocampus leading to abnormal synaptic plasticity (Costenla et al, 2011;Kaster et al, 2015), and A 2A R blockade prevent memory impairment in conditions such as stress, aging, or Alzheimer's disease (eg Batalha et al, 2013;Laurent et al, 2016;Oor et al, 2015;Prediger et al, 2005), an effect mimicked by caffeine (a nonselective adenosine receptor antagonist) both in animal models and in humans (reviewed in Cunha and Agostinho, 2010;Chen, 2014).…”