Novel Players in the Aging Synapse: Impact on Cognition

Abstract

While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho-and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A 2A receptors (A 2A R) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A 2A R-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A 2A R in the control of mGluR5-dependent NMDAR activation and subsequent Ca 2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.

Effects of Caffeine on Event-Related Potentials and Neuropsychological Indices After Sleep Deprivation

“…Caffeine maintains a higher dopamine concentration especially in those brain areas linked with “attention.” Depending on the neurotransmitter system, caffeine can affect different brain areas with different functions (Meeusen et al, 2013 ). Usually, caffeine has delayed effect about 3–4 h of half-life (Knutti et al, 1981 , 1982 ; Nehlig, 2016 ), caffeine’s behavioral effects and the significant increase in psychomotor performance it causes have been documented in a large body of literature, in addition to improvements in attention- (Temido-Ferreira et al, 2019 ; Alasmari, 2020 ; Franceschini et al, 2020 ; Irwin et al, 2020 ; Jahrami et al, 2020 ), mood-, and vigor-based tasks (Dietz and Dekker, 2017 ; Shabir et al, 2018 ; Alasmari, 2020 ). Moreover, Beaumont et al ( 2005 ) found that the action of caffeine both shortened response times and reduced the number of errors on psychomotor tests, which indicates that caffeine has a global action on information processing and divided attention management (Beaumont et al, 2005 ; Wilhelmus et al, 2017 ).…”

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A2A Receptor-Mediated Effects in the Central Nervous System

“…In the same way, A 2A Rs are upregulated in Alzheimer's disease, both in animal models and in the brain of patients (Arendash et al, 2006;Albasanz et al, 2008;Orr et al, 2015;Temido-Ferreira et al, 2020). More interestingly, during aging both STEP and A 2A Rs are upregulated and show an enhanced activity in animal models and in the human aged brain, and inhibition of STEP activity or the blockade of A 2A Rs improved memory performances (Castonguay et al, 2018;Orr et al, 2018;Ferré and Ciruela, 2019;Temido-Ferreira et al, 2019;Temido-Ferreira et al, 2020). Finally, STEP over-expression induced memory impairment in adult mice (Castonguay et al, 2018), and the same occurs in conditions of increased A 2A Rs activation (Gimenez-Llort et al, 2007;Li et al, 2015;Pagnussat et al, 2015).…”

“…Thus, one important conclusion is that the modulation of STEP activity could contribute to the effects of A 2A Rs on cognitive functions (Chen, 2014;Uchida et al, 2014;Temido-Ferreira et al, 2019). As for Parkinson's disease, an interesting consideration is that long-term treatment of patients with istradefylline could result not only in the improvement of motor deficits but also in beneficial effects on cognitive dysfunction, and that the inhibition of STEP could play a major role in this effect.…”

An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?

“…In this condition, there is a rise of A 2A receptor and G proteins-coupling, leading to an increase in glutamate release, mGluR5-dependent NMDA receptor overstimulation, and enhanced calcium influx responsible for synaptic alterations and memory dysfunction ( Temido-Ferreira et al, 2020 ). These findings suggest a role for this receptor subtype in the pathogenesis of different neurocognitive disorders and specifically AD ( Costenla et al, 2011 ; Rebola et al, 2011 ; Horgusluoglu-Moloch et al, 2017 ; Temido-Ferreira et al, 2019 ). Indeed, synaptic dysfunction and damage are key features in early AD ( Selkoe, 2002 ; Coleman et al, 2004 ).…”

“…As for its synaptic expression in spite of episodic evidence ( Canas et al, 2018 ), it is still debatable if there is A 2A receptors expression in synapses, although it is well established that A 2A receptors are located in hippocampal synapses, with a density about 20–time lower than in the striatum ( Lopes et al, 2004 ; Rebola et al, 2005 ). Although in healthy human brains the A 2A receptor may exert protective functions, by regulating other proteins as BDNF, its signaling is strongly modified in the hippocampus following aging ( Rebola et al, 2003 ; Tebano et al, 2010 ; Temido-Ferreira et al, 2019 ; Temido-Ferreira et al, 2020 ). In this condition, there is a rise of A 2A receptor and G proteins-coupling, leading to an increase in glutamate release, mGluR5-dependent NMDA receptor overstimulation, and enhanced calcium influx responsible for synaptic alterations and memory dysfunction ( Temido-Ferreira et al, 2020 ).…”