Dataset Information

The microglial P2Y₆ receptor mediates neuronal loss and memory deficits in neurodegeneration.

ABSTRACT: Microglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The microglial P2Y₆ receptor (P2Y₆R) - activated by extracellular UDP released by stressed neurons - is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal and memory loss, and this is all prevented by knockout of P2Y₆R. In a chronic tau model of neurodegeneration (P301S TAU mice), P2Y₆R knockout prevented TAU-induced neuronal and memory loss. In vitro, P2Y₆R knockout blocked microglial phagocytosis of live but not dead targets and reduced tau-, Aβ-, and UDP-induced neuronal loss in glial-neuronal cultures. Thus, the P2Y₆ receptor appears to mediate Aβ- and tau-induced neuronal and memory loss via microglial phagocytosis of neurons, suggesting that blocking this receptor may be beneficial in the treatment of neurodegenerative diseases.

SUBMITTER: Puigdellivol M

PROVIDER: S-EPMC8733854 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration.

Puigdellívol Mar M Milde Stefan S Vilalta Anna A Cockram Tom O J TOJ Allendorf David H DH Lee Jeffrey Y JY Dundee Jacob M JM Pampuščenko Katryna K Borutaite Vilmante V Nuthall Hugh N HN Brelstaff Jack H JH Spillantini Maria Grazia MG Brown Guy C GC

Cell reports 20211201 13

Microglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The microglial P2Y6 receptor (P2Y6R) - activated by extracellular UDP released by stressed neurons - is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal ...[more]

PMID: 34965424

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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.

Dataset Information

The microglial P2Y₆ receptor mediates neuronal loss and memory deficits in neurodegeneration.

Publications

The microglial P2Y<sub>6</sub> receptor mediates neuronal loss and memory deficits in neurodegeneration.

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