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

Puigdellívol, Mar; Milde, Stefan; Vilalta, Anna; Cockram, Tom O. J.; Allendorf, David H.; Lee, Young Seok; Dundee, Jacob M.; Pampuščenko, Katryna; Borutaitė, Vilmantė; Nuthall, Hugh; Brelstaff, Jack; Spillantini, Maria Grazia; Brown, Guy C.

doi:10.1016/j.celrep.2021.110148

Cited by 48 publications

(52 citation statements)

References 47 publications

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“…Additionally, P2Y6R-mediated phagocytosis mediates the removal of neuronal debris in a cerebral stroke model [397]. Although these findings demonstrate the protective role of P2Y6R, microglial phagocytosis response induced by this receptor has been shown to exacerbate AD pathology by promoting microglial phagocytosis of stressed but viable neurons, which are capable of releasing UDP [398]. In mixed neuron/glia culture, the use of the P2Y6R antagonist MRS2578 delayed the neuronal loss induced by Aβ, and this effect was mediated by inhibiting microglial phagocytosis response.…”

Section: P2y Receptorsmentioning

confidence: 87%

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Wendimu

Hooks

2022

Cells

144

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Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

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Section: P2y Receptorsmentioning

confidence: 87%

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Wendimu

Hooks

2022

Cells

144

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“…We also found that injection of amyloid beta into the brains of mice induced microglial phagocytosis of neurons, loss of neurons, and memory deficits, all of which were prevented in P2Y6R knockout mice [26]. Similarly, we used a chronic model of neurodegeneration (i.e., mice expressing P301S TAU) and found that crossing these mice with P2Y6R knockout mice prevented the brain neuronal loss and memory deficits [26]. Thus, we were interested to know whether P2Y6R knockout could prevent the loss of peri-infarct neurons after transient brain ischemia.…”

Section: Resultsmentioning

confidence: 65%

“…More recently, we showed that chronic, peripheral LPS induced neuronal loss in the brains of mice and this neuronal loss was prevented by knockout of P2Y6R [25]. We also found that injection of amyloid beta into the brains of mice induced microglial phagocytosis of neurons, loss of neurons, and memory deficits, all of which were prevented in P2Y6R knockout mice [26]. Similarly, we used a chronic model of neurodegeneration (i.e., mice expressing P301S TAU) and found that crossing these mice with P2Y6R knockout mice prevented the brain neuronal loss and memory deficits [26].…”

Section: Resultsmentioning

confidence: 79%

“…We have previously shown that P2Y 6 R knockout prevents neuronal loss, memory loss, and microglial phagocytosis of neurons induced by injection of amyloid beta into the mouse brain [26], reduces neuronal loss and memory loss when crossed with the P301S TAU model of tauopathy [26], and prevents dopaminergic neuronal loss in the substantia nigra induced by peripheral endotoxin [25]. Similarly, injection of the P2Y 6 R antagonist MRS2578 into the brain prevented LPS/endotoxin-induced neuronal loss [24], and others have found that injection of the P2Y 6 R antagonist MRS2578 into the brain prevented 6-hydroxydopamineinduced loss of dopaminergic neuronal loss in the substantia nigra [29].…”

Section: Discussionmentioning

confidence: 99%

“…P2Y 6 R has been found to promote cytokine and chemokine release from monocytes, and thus has been suggested to be pro-inflammatory in microglia [23,30]. However, inhibition or knockout of P2Y 6 R has no apparent effect on the inflammatory response of microglia [24,26,31]. On the other hand, P2Y 6 R may regulate functions other than microglial phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

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Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain

Milde

Brown

2022

IJMS

Self Cite

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After stroke, there is a delayed neuronal loss in brain areas surrounding the infarct, which may in part be mediated by microglial phagocytosis of stressed neurons. Microglial phagocytosis of stressed or damaged neurons can be mediated by UDP released from stressed neurons activating the P2Y6 receptor on microglia, inducing microglial phagocytosis of such neurons. We show evidence here from a small trial that the knockout of the P2Y6 receptor, required for microglial phagocytosis of neurons, prevents the delayed neuronal loss after transient, focal brain ischemia induced by endothelin-1 injection in mice. Wild-type mice had neuronal loss and neuronal nuclear material within microglia in peri-infarct areas. P2Y6 receptor knockout mice had no significant neuronal loss in peri-infarct brain areas seven days after brain ischemia. Thus, delayed neuronal loss after stroke may in part be mediated by microglial phagocytosis of stressed neurons, and the P2Y6 receptor is a potential treatment target to prevent peri-infarct neuronal loss.

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iPSC‐derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss

Penney,

Ralvenius,

Loon

et al. 2023

Glia

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Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human‐induced pluripotent stem cell‐derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser‐induced injury model in neuron–microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

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

Cited by 48 publications

References 47 publications

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Microglia Phenotypes in Aging and Neurodegenerative Diseases

Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain

iPSC‐derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss

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