TY - JOUR
T1 - P2X7R influences tau aggregate burden in human tauopathies and shows distinct signalling in microglia and astrocytes
AU - Beltran-Lobo, Paula
AU - Hughes, Martina M.
AU - Troakes, Claire
AU - Croft, Cara L.
AU - Rupawala, Huzefa
AU - Jutzi, Daniel
AU - Ruepp, Marc David
AU - Jimenez-Sanchez, Maria
AU - Perkinton, Michael S.
AU - Kassiou, Michael
AU - Golde, Todd E.
AU - Hanger, Diane P.
AU - Verkhratsky, Alexei
AU - Perez-Nievas, Beatriz G.
AU - Noble, Wendy
N1 - Funding Information:
We thank the late Peter Davies for tau antibodies, George Chennell of the Wohl Cellular Imaging Centre at King's College London (including the Nikon Ti-E eclipse microscope funded by Alzheimer's Research UK; ARUK-EG2013B-1) for technical support, and the London Neurodegenerative Disease Brain Bank. The RNA-seq results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). The Mayo RNA-seq study was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsońs Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimeŕs Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinsońs Research. The AD knowledge portal thanks Drs. Jada Lewis, Karen Duff, David Westaway and David Borchelt for generating lines of transgenic mice and providing access to them.
Funding Information:
This work was funded by Alzheimer’s Research UK (ARUK-PhD2018-002) to WN and BGP-N, Van Geest Charitable Foundation funding to BGP-N, Astra Zeneca (WPAM216014SW) to WN, DPH and MSP, a Medical Research Council Transition Award to MJ-S (MR/V036947/1), the National Health and Medical Research Council (APP1154692) to MK, a Race Against Dementia Alzheimer’s Research UK fellowship (ARUK-RADF2019A-003) to CLC, and the UK Dementia Research Institute (UK DRI-6005) to M−DR, where CLC is also based, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The London Neurodegenerative Disease Brain Bank receives funding from the Medical Research Council and the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society. This study was also supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
We thank the late Peter Davies for tau antibodies, George Chennell of the Wohl Cellular Imaging Centre at King's College London (including the Nikon Ti-E eclipse microscope funded by Alzheimer's Research UK; ARUK-EG2013B-1) for technical support, and the London Neurodegenerative Disease Brain Bank. The RNA-seq results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). The Mayo RNA-seq study was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsońs Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimeŕs Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinsońs Research. The AD knowledge portal thanks Drs. Jada Lewis, Karen Duff, David Westaway and David Borchelt for generating lines of transgenic mice and providing access to them.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/11
Y1 - 2023/11
N2 - The purinoceptor P2X7R is a promising therapeutic target for tauopathies, including Alzheimer's disease (AD). Pharmacological inhibition or genetic knockdown of P2X7R 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 P2X7R and therefore the mechanism of action is unresolved. Here, we show that P2X7R 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. P2X7R 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, P2X7R activation modulates the NLRP3 inflammasome pathway by promoting the formation of active complexes and release of IL-1β. In astrocytes, P2X7R activates NFκB 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 P2X7R in a disease-relevant context, we expressed wild-type or FTD-causing mutant forms of tau in mouse organotypic brain slice cultures. Inhibition of P2X7R reduces insoluble tau levels without altering soluble tau phosphorylation or synaptic localisation, suggesting a non-cell autonomous role of glial P2X7R on pathological tau aggregation. These findings support further investigations into the cell-type specific effects of P2X7R-targeting therapies in tauopathies.
AB - The purinoceptor P2X7R is a promising therapeutic target for tauopathies, including Alzheimer's disease (AD). Pharmacological inhibition or genetic knockdown of P2X7R 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 P2X7R and therefore the mechanism of action is unresolved. Here, we show that P2X7R 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. P2X7R 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, P2X7R activation modulates the NLRP3 inflammasome pathway by promoting the formation of active complexes and release of IL-1β. In astrocytes, P2X7R activates NFκB 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 P2X7R in a disease-relevant context, we expressed wild-type or FTD-causing mutant forms of tau in mouse organotypic brain slice cultures. Inhibition of P2X7R reduces insoluble tau levels without altering soluble tau phosphorylation or synaptic localisation, suggesting a non-cell autonomous role of glial P2X7R on pathological tau aggregation. These findings support further investigations into the cell-type specific effects of P2X7R-targeting therapies in tauopathies.
KW - Alzheimer's disease
KW - Astrocyte
KW - Human brain
KW - Microglia
KW - P2XR
KW - RNAScope
KW - Tauopathy
UR - http://www.scopus.com/inward/record.url?scp=85171645363&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2023.09.011
DO - 10.1016/j.bbi.2023.09.011
M3 - Article
C2 - 37716378
AN - SCOPUS:85171645363
SN - 0889-1591
VL - 114
SP - 414
EP - 429
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -