Publicação
Alterations in synaptic plasticity and memory in aging and Alzheimer's disease: the role of adenosine A2A receptors
| Resumo: | The lifespan of the human population has been steadily on the rise for several years, with a 20-year increase from 1960 to the present day. With aging, various health problems arise, with memory loss being one of the most prevalent. This mnemonic decline has been associated with deterioration in hippocampal synaptic plasticity, particularly in long-term potentiation (LTP) and long-term depression (LTD), with pathologies such as Alzheimer's disease (AD) showing synaptic deficits at an early stage. In AD there is an increase in extracellular levels of adenosine, a neuromodulator that plays a vital role in memory processing through its inhibitory A1 receptor (A1R) and facilitatory A2A receptor (A2AR), and the overexpression of the latter is sufficient to cause mnemonic damage, while its blockade is capable of reversing this damage. Extracellular adenosine is mostly derived from the processing of adenosine 5’-triphosphate (ATP) released during brain activity, with the vesicular nucleotide transporter (VNUT) regulating the storage of this ATP in synaptic vesicles and its frequency-dependent release, and the equilibrative nucleoside transporter 1 (ENT1) modulating the availability of adenosine through the transport across the membrane.The aim of this study was to assess the impact of A2AR on aging and in AD. Furthermore, since available extracellular adenosine is dependent on the activity of both ENT1 and VNUT, we also probed for alterations in these two transporters after the induction of AD-like conditions.Using adult (12-months-old) and aged (24-months-old) mice, we observed that genetically eliminating A2AR in forebrain neurons had a minimal impact on memory and synaptic plasticity in these animals. However, in a mouse model of AD obtained through intracerebroventricular (I.C.V.) injection with oligomeric Aβ1-42, considered a culprit agent for AD onset, removing A2AR from the hippocampus normalized synaptic plasticity. Regarding ENT1, its inhibition leads to disturbances in LTP, regardless of age and the presence/absence of A2AR. Moreover, in AD conditions, ENT1 density was found to be increased. Conversely, there was a decrease in VNUT levels in our AD mouse model.Taken together, these results provide new insights into the complex role of A2AR in memory and synaptic plasticity, emphasizing that its dysfunction is particularly pronounced under conditions of neuronal insult and is not specifically influenced by aging itself, as well as highlighting the importance of ENT1 and VNUT as possible key players in synaptic dysregulation. |
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| Autores principais: | Olaio, Simão Pedro Alves |
| Assunto: | Adenosine A2 receptors Aging Memory Alzheimer's disease Adenosine modulation Receptores A2 de adenosina Envelhecimento Memória Doença de Alzheimer Modulação de adenosina |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | The lifespan of the human population has been steadily on the rise for several years, with a 20-year increase from 1960 to the present day. With aging, various health problems arise, with memory loss being one of the most prevalent. This mnemonic decline has been associated with deterioration in hippocampal synaptic plasticity, particularly in long-term potentiation (LTP) and long-term depression (LTD), with pathologies such as Alzheimer's disease (AD) showing synaptic deficits at an early stage. In AD there is an increase in extracellular levels of adenosine, a neuromodulator that plays a vital role in memory processing through its inhibitory A1 receptor (A1R) and facilitatory A2A receptor (A2AR), and the overexpression of the latter is sufficient to cause mnemonic damage, while its blockade is capable of reversing this damage. Extracellular adenosine is mostly derived from the processing of adenosine 5’-triphosphate (ATP) released during brain activity, with the vesicular nucleotide transporter (VNUT) regulating the storage of this ATP in synaptic vesicles and its frequency-dependent release, and the equilibrative nucleoside transporter 1 (ENT1) modulating the availability of adenosine through the transport across the membrane.The aim of this study was to assess the impact of A2AR on aging and in AD. Furthermore, since available extracellular adenosine is dependent on the activity of both ENT1 and VNUT, we also probed for alterations in these two transporters after the induction of AD-like conditions.Using adult (12-months-old) and aged (24-months-old) mice, we observed that genetically eliminating A2AR in forebrain neurons had a minimal impact on memory and synaptic plasticity in these animals. However, in a mouse model of AD obtained through intracerebroventricular (I.C.V.) injection with oligomeric Aβ1-42, considered a culprit agent for AD onset, removing A2AR from the hippocampus normalized synaptic plasticity. Regarding ENT1, its inhibition leads to disturbances in LTP, regardless of age and the presence/absence of A2AR. Moreover, in AD conditions, ENT1 density was found to be increased. Conversely, there was a decrease in VNUT levels in our AD mouse model.Taken together, these results provide new insights into the complex role of A2AR in memory and synaptic plasticity, emphasizing that its dysfunction is particularly pronounced under conditions of neuronal insult and is not specifically influenced by aging itself, as well as highlighting the importance of ENT1 and VNUT as possible key players in synaptic dysregulation. |
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