Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and synaptic dysfunction. Adenosine is an important homeostatic modulator that controls the bioenergetic network in the brain through regulating receptor-evoked signaling pathways, bioenergetic machineries, and epigenetic-mediated gene regulation. Equilibrative nucleoside transporter 1 (ENT1) is a major adenosine transporter that recycles adenosine from the extracellular space. In the present study, we report that a small adenosine analogue (designated J4) that inhibited ENT1 prevented the decline in spatial memory in an AD mouse model (APP/PS1). Electrophysiological and biochemical analyses further demonstrated that chronic treatment with J4 normalized the impaired basal synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses as well as the aberrant expression of synaptic proteins (e.g., NR2A and NR2B), abnormal neuronal plasticity-related signaling pathways (e.g., PKA and GSK3β), and detrimental elevation in astrocytic AR expression in the hippocampus and cortex of APP/PS1 mice. In conclusion, our findings suggest that modulation of adenosine homeostasis by J4 is beneficial in a mouse model of AD. Our study provides a potential therapeutic strategy to delay the progression of AD.

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

“…Several studies have shown that the levels of A 2A R expression change in AD is up to five times higher than those of normal levels (Orr et al, ). Also, in vivo data from traumatic brain injury or amyloid‐based models have demonstrated a similar range of A 2A R upsurge ranging from 1.5 to 12 fold (Zhao et al, ; Orr et al, ; Faivre et al, ; Lee et al, ). One could therefore argue that the A 2A R overexpression reached in our study is beyond the changes found in pathophysiological conditions.…”

“…A 2A R is a modulator of several physiological responses essential to brain homeostasis such as blood brain barrier maintenance, neurotransmitter release, and inflammation (Gołembiowska et al, ; Ouyang et al, ; Bhamidipati et al, ; Kim & Bynoe, ), processes that are highly associated with neurodegenerative diseases, such as AD and PD (Cunha, ). The relationship between A 2A R and AD in the control of cognitive impairment has been extensively observed in several experimental models (Canas et al, ; Laurent et al, 2014; Laurent et al, 2014; Lee et al, ; Silva et al, ). Upregulation of A 2A R in neurons was shown to induce aberrant phenotypic alterations during aging and in the early stages of AD (Temido‐Ferreira et al, ).…”

“…In physiological conditions, A 2A Rs play an important role in fine synaptic tuning (Cunha, ): neuronal A 2A Rs regulated NMDA receptors to control synaptic plasticity processes (Rebola et al, ; Temido‐Ferreira et al, ) while astrocytic A 2A Rs control glutamate and GABA uptakes (Lopes et al, ; Matos et al, , ; Cristovao‐Ferreira et al, ), regulating the excitatory/inhibitory balance. Interestingly, reactive astrocytes have been shown to exhibit adenosine A 2A R upregulation in different neuropathological conditions such as AD, epilepsy, Sandhoff disease, and also in animal models of AD and PD (Orr et al, , ; Barros‐Barbosa et al, ; Zhao et al, ; Faivre et al, ; Lee et al, ; Yu et al, ; Hu et al, ; Ogawa et al, ). However, the pathophysiological impact of such astrocytic A 2A R upsurge remains unclear.…”

Novel Players in the Aging Synapse: Impact on Cognition

“…170 Adenosine augmentation has been found beneficial in multiple neurological disorders, including AD. 171,172 However, further comprehension of the mechanism and the putative effects on adenosine receptors and downstream signaling pathways are crucial at this stage.…”

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

“…Recent studies suggest that inactivated autophagy-related proteins in damaged neurons [14] represent a suitable target for experimental NDD therapy [15]. Although there is extensive literature on the accumulation of toxic proteins inside neuronal cells as a result of autophagy repression and its pharmacological correction [16], relatively few studies have addressed the possibility of targeting neuronal cells with aberrant signaling [17][18][19][20][21] by using alternate approaches, such as gene therapy. Below, we summarized the benefits of gene therapy application for NDD treatment.…”