Neuronal A2A Receptor Exacerbates Synapse Loss and Memory Deficits in APP/PS1 Mice
A2A Adenosine Receptor Exacerbates Synaptic Loss and Memory Deficits in APP/PS1 Mice
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with progressive cognitive decline, characterized by the deposition of extracellular β-amyloid (Aβ) plaques and the accumulation of hyperphosphorylated tau protein in neurons. Some epidemiological studies suggest that caffeine intake is negatively correlated with the risk of age-related cognitive impairment and subsequent AD. Caffeine is considered protective, possibly through blocking adenosine A2A receptors (A2AR), which show increased expression in the brains of AD patients. This paper aims to understand the mechanism of early A2AR in AD pathology development, focusing particularly on its effects on synaptic and memory deficits.
Research Background and Source
This study was jointly conducted by Victoria Gomez-Murcia, Agathe Launay, and several other scholars from various neuroscience research institutions in France and Switzerland, such as the UMR-S1172 Lille Neuroscience & Cognition team and the Laboratoire de Neuroscience Cognitives et Adaptatives team. The research was published in the journal “Brain” on July 5, 2024, with the aim of exploring the effects of A2AR in AD model mice.
Research Process and Experimental Methods
Animal Model
The study used Appswe/PS1de9 transgenic mice (referred to as APP/PS1), which received bilateral hippocampal injections at 3 months of age using AAV2/5 viral vectors to overexpress A2AR in the hippocampus. Four genotypes of mice were used: wild-type (WT), A2AR upregulated mice, APP/PS1 mice, and APP/PS1 A2AR upregulated mice. All mice were raised under standard laboratory conditions with adequate food and water.
Behavioral Analysis
At 5 to 6 months of age, mice underwent spatial memory tests through various behavioral experiments (such as Y-maze and Barnes maze). The study found that while WT, A2AR, and APP/PS1 mice showed normal spatial memory abilities, APP/PS1 A2AR mice exhibited significant spatial memory deficits at 6 months of age, indicating that early A2AR upregulation exacerbated behavioral impairments in APP/PS1 mice.
Tissue Sample Processing
Mice were anesthetized and perfused at 6 months of age, followed by brain tissue sectioning and freezing for subsequent biochemical and mRNA analyses. To study the effects of nutritional pathology, mice were divided into control and experimental groups, and their tissue samples were analyzed by immunohistochemistry, Western blot, transmission electron microscopy, and proteomics.
Transcriptomics and Proteomics Analysis
RNA sequencing was used to analyze gene expression changes in the hippocampus, while nano-liquid chromatography-tandem mass spectrometry was employed to analyze protein expression levels. The study found significant differences in gene and protein expression between APP/PS1 and APP/PS1 A2AR mice. Genes showing population-specific changes in APP/PS1 A2AR mice mainly involved immune responses and mitochondrial function, with synaptic-related genes showing significant downregulation.
Main Research Findings
Exacerbation of Memory Deficits
Behavioral analysis revealed that A2AR upregulation in the hippocampus exacerbated early spatial memory deficits in APP/PS1 mice. This aligns with previous studies showing that A2AR downregulation can restore hippocampal plasticity in APP/PS1 mice.
Pathological Changes
In pathological tests, A2AR upregulation did not significantly alter the production and aggregation of APP white matter (Aβ) but significantly increased tau protein phosphorylation around amyloid plaques, potentially explaining the exacerbation of synaptic loss and memory deficits. Immunohistochemistry results showed changes in both neuronal and non-neuronal cells in APP/PS1 A2AR mice, particularly enhanced neuroinflammatory responses, excitatory synaptic loss, and impaired mitochondrial function.
Molecular Mechanisms
Through transcriptomic and proteomic analyses, the study revealed that gene modules involved in immune responses and mitochondrial function were significantly affected in A2AR upregulated mice. The upregulation of immune-related genes may lead to synaptic loss, explaining the associated memory deficits. Additionally, the downregulation of mitochondria-related genes may be associated with reduced energy production and synaptic structural loss.
Research Conclusions and Significance
Overall, this study provides compelling evidence that A2AR dysfunction in neurons, similar to observations in patients’ brains, contributes to amyloid-related pathological changes, suggesting A2AR as a potential therapeutic target for alleviating cognitive impairments in this neurodegenerative disease. In-depth research on A2AR may lead to the development of novel therapeutic strategies targeting early synaptic loss in AD, potentially bringing better prevention and treatment outcomes for patients.
Research Highlights
- Exacerbation of Memory Deficits: A2AR upregulation exacerbated spatial memory deficits in APP/PS1 mice, revealing its crucial role in early cognitive decline.
- Specific Mechanisms of Pathological Changes: The study detailed immune responses, synaptic loss, and mitochondrial dysfunction as the main pathological changes caused by A2AR upregulation.
- Potential Therapeutic Target: A2AR is emphasized as an important therapeutic target for early cognitive impairment in AD, providing direction for future drug development.
This study also highlights the critical role of mitochondrial and synaptic changes in AD synaptic pathology, reminding researchers of the need for more in-depth exploration of these change mechanisms and translational research for clinical applications in the future.