Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

Abstract

Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

“…Previous studies have suggested that ENT1 and ENT2 play critical roles in the control of immune responses, mitochondrial activity, and neurological functions. Pharmacological inhibition or genetic deficiency of ENT1 or ENT2 showed beneficial roles in preventing lipopolysaccharide (LPS)-induced neuroinflammation [ 244 ], LPS-induced acute pulmonary inflammation [ 178 ], Pseudomonas aeruginosa–induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation [ 45 ], and disease-associated neuroinflammation [ 46 , 144 ]. In addition, genetic removal of ENT1 reduced essential astrocytic proteins (e.g., glial fibrillary acidic protein, excitatory amino acid transporter 2 (EAAT2), and aquaporin 4) critical for astrocyte functions [ 110 ].…”

“…Ample evidence suggests that adenosine homeostasis is important for cellular metabolism and has been implicated in the status of AMPK activation [ 46 , 171 , 192 , 207 ]. AMPK is a key energy sensor and regulator in cells [ 108 ].…”

“…Altered expression of adenosine receptors (including A 1 R and A 2A R) has been found in the frontal cortex of AD patients and AD mice (APP/PS1) [ 5 , 144 , 225 ]. The dysregulated adenosinergic system has long been considered a possible target for the development of new treatments for AD [ 46 , 143 , 144 , 174 , 186 , 187 ]. In particular, suppression of A 2A R or A 1 R provides beneficial effects on different molecular aspects related to the cognitive functions of AD mice [ 67 , 79 , 143 , 187 ].…”

“…Here, we focus on several proteins involved in adenosine metabolism that may serve as novel drug targets for AD; namely, ENT1, which is the most well-characterized adenosine transporter in the brain. Two recent studies reported that chronic treatment with an orally active, BBB-permeable small ENT1 inhibitor (J4) attenuated impaired cognitive function, inferior neuroplasticity, and elevated neuroinflammation in two AD mouse models (APP/PS1 and THY-Tau22) [ 46 , 144 ]. Other enzymes involved in adenosine metabolism (ADA, ADK, CD39 and CD73) are also abnormally affected in AD, similar to other neurodegenerative diseases (Table 1 ).…”

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

“…Dysregulation of AMPK either positively or negatively disrupts this synaptic plasticity in response to neuronal activation and may induce synaptic loss and impair cognitive functions (Marinangeli et al, 2018 ; Domise et al, 2019 ; Wang et al, 2019 ). Given that aberrant AMPK activation due to energy deficiency has been reported in degenerating neurons of several neurodegenerative diseases (including Alzheimer’s disease AD; Chen et al, 2009 ; Mairet-Coello et al, 2013 ; Ma et al, 2014 ; Chang et al, 2021 ), Huntington’s disease (HD; Ju et al, 2011 , 2014 ), and amyotrophic lateral sclerosis (ALS; Lim et al, 2012 ; Liu et al, 2015a , b ), a better understanding of the function and regulation of AMPK during neurodegeneration may provide potential targets for the development of new treatments for neurodegeneration diseases.…”