| First Author | Beltran-Lobo P | Year | 2023 |
| Journal | Brain Behav Immun | Volume | 114 |
| Pages | 414-429 | PubMed ID | 37716378 |
| Mgi Jnum | J:341233 | Mgi Id | MGI:7532361 |
| Doi | 10.1016/j.bbi.2023.09.011 | Citation | Beltran-Lobo P, et al. (2023) P2X(7)R influences tau aggregate burden in human tauopathies and shows distinct signalling in microglia and astrocytes. Brain Behav Immun 114:414-429 |
| abstractText | The purinoceptor P2X(7)R is a promising therapeutic target for tauopathies, including Alzheimer's disease (AD). Pharmacological inhibition or genetic knockdown of P2X(7)R ameliorates cognitive deficits and reduces pathological tau burden in mice that model aspects of tauopathy, including mice expressing mutant human frontotemporal dementia (FTD)-causing forms of tau. However, disagreements remain over which glial cell types express P2X(7)R and therefore the mechanism of action is unresolved. Here, we show that P2X(7)R protein levels increase in human AD post-mortem brain, in agreement with an upregulation of P2RX7 mRNA observed in transcriptome profiles from the AMP-AD consortium. P2X(7)R protein increases mirror advancing Braak stage and coincide with synapse loss. Using RNAScope we detect P2RX7 mRNA in microglia and astrocytes in human AD brain, including in the vicinity of senile plaques. In cultured microglia, P2X(7)R activation modulates the NLRP3 inflammasome pathway by promoting the formation of active complexes and release of IL-1beta. In astrocytes, P2X(7)R activates NFkappaB signalling and increases production of the cytokines CCL2, CXCL1 and IL-6 together with the acute phase protein Lcn2. To further explore the role of P2X(7)R in a disease-relevant context, we expressed wild-type or FTD-causing mutant forms of tau in mouse organotypic brain slice cultures. Inhibition of P2X(7)R reduces insoluble tau levels without altering soluble tau phosphorylation or synaptic localisation, suggesting a non-cell autonomous role of glial P2X(7)R on pathological tau aggregation. These findings support further investigations into the cell-type specific effects of P2X(7)R-targeting therapies in tauopathies. |
