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Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
- Source :
- Brain: A Journal of Neurology; Aug2024, Vol. 147 Issue 8, p2691-2705, 15p
- Publication Year :
- 2024
-
Abstract
- Early pathological upregulation of adenosine A<subscript>2A</subscript> receptors (A<subscript>2A</subscript>Rs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A<subscript>2A</subscript>R in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A<subscript>2A</subscript>R in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A<subscript>2A</subscript>R dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A<subscript>2A</subscript>R as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder. [ABSTRACT FROM AUTHOR]
- Subjects :
- ALZHEIMER'S disease
MEMORY disorders
AMYLOID plaque
MEMORY loss
COGNITION disorders
Subjects
Details
- Language :
- English
- ISSN :
- 00068950
- Volume :
- 147
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Brain: A Journal of Neurology
- Publication Type :
- Academic Journal
- Accession number :
- 178887933
- Full Text :
- https://doi.org/10.1093/brain/awae113