Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease

Lan Ting Zhou; Dan Liu; Hui Cong Kang; Lu Lu; He Zhou Huang; Wen Qing Ai; Yang Zhou; Man Fei Deng; Hao Li; Zhi Qiang Liu; Wei Feng Zhang; Ya Zhuo Hu; Zhi Tao Han; Hong Hong Zhang; Jian Jun Jia; Avijite Kumer Sarkar; Saldin Sharaydeh; Jie Wang; Heng Ye Man; Marcel Schilling; Lars Bertram; Youming Lu; Ziyuan Guo; Ling Qiang Zhu

doi:10.1126/sciadv.abq7105

Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease

Lan Ting Zhou, Dan Liu, Hui Cong Kang, Lu Lu, He Zhou Huang, Wen Qing Ai, Yang Zhou, Man Fei Deng, Hao Li, Zhi Qiang Liu, Wei Feng Zhang, Ya Zhuo Hu, Zhi Tao Han, Hong Hong Zhang, Jian Jun Jia, Avijite Kumer Sarkar, Saldin Sharaydeh, Jie Wang, Heng Ye Man, Marcel SchillingLars Bertram, Youming Lu^*, Ziyuan Guo^*, Ling Qiang Zhu^*

^*Corresponding author for this work

Institute of Neurogenetics

42 Citations (Scopus)

Abstract

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyper-phosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Original language	English
Article number	eabq7105
Journal	Science Advances
Volume	9
Issue number	16
Pages (from-to)	eabq7105
DOIs	https://doi.org/10.1126/sciadv.abq7105
Publication status	Published - 21.04.2023

Funding

Acknowledgments:TheAK OmicewereagiftfromJ.SchnermannatNIDDK/NIH.W ethankall thetechniciansandcorefacilityintheAnalyticalandT es tingCenter,HuazhongUniversityof ScienceandT echnology .Funding:ThisstudywaspartiallysupportedbytheNationalKey ResearchandDevelopmentProgramofChina(grantno.2019YFE0121200),theNationalNatural ScienceFoundationofChina(grantnos.82030032,82261138555,32070960,81761138043, 81901103,31721002,and81961128005),theTop-NotchYoungTalentsProgramofChinaof 2014,theAcademicFrontierYouthT eam ofHuazhongUniversityofScienceandT echnology to L.-Q.Z.,theHubeiProvincialNaturalScienceFoundation(2022CFA004toL.-Q.Z.),theNIH(grant no. NS122169), the Cincinnati Children’s Hospital Medical Center (CCHMC) Trustee Grant A ward,andtheCCHMCCenterforPediatricGenomicsA wardtoZ.G.Authorcontributions:L.-Q.Z.initiatedanddesignedthestudy.L.-Q.Z.andD.L.supervisedthestudy.L.-T .Z., H.-C.K.,H.-Z.H.,W .-Q.A., Y .Z., andW .-F .Z. performedthemolecularbiologicalexperimentsandanimal experiments.L.-T .Z. andZ.-Q.L.analyzedtheRNA-seqdata.M.-F .D., H.L.,andL.-T .Z. performed the electrophysiological recordings. L.L., A.K.S., S.S., M.S., and Z.G. generated AD iPSC lines, performedbiochemicalandelectrophysiologicalexperimentsusingiPSCs,andanalyzedthe data.Y .-Z.H., Z.-T .H., H.-H.Z.,andJ.-J.J.providedthehumantissuesamples.L.B.andM.S. analyzedtheexpressionofMEF2candADORA1inhumansamples.L.-T .Z., H.-C.K.,Y .L., D.L.,J.W ., H.-Y .M., andL.-Q.Z.analyzedthedata.L.-Q.Z.,L.-T .Z., D.L.,andZ.G.wrotethemanuscript. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:TheRNA-seqdataareaccessiblethroughGEOSeriesaccessionnumber GSE193826(www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193826).Alldataneededto evaluatetheconclusionsinthepaperarepresentinthepaperand/ortheSupplementary Materials. This study was partially supported by the National Key Research and Development Program of China (grant no. 2019YFE0121200), the National Natural Science Foundation of China (grant nos. 82030032, 82261138555, 32070960, 81761138043, 81901103, 31721002, and 81961128005), the Top-Notch Young Talents Program of China of 2014, the Academic Frontier Youth Team of Huazhong University of Science and Technology to L.-Q.Z., the Hubei Provincial Natural Science Foundation (2022CFA004 to L.-Q.Z.), the NIH (grant no. NS122169), the Cincinnati Children’s Hospital Medical Center (CCHMC) Trustee Grant Award, and the CCHMC Center for Pediatric Genomics Award to Z.G.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1126/sciadv.abq7105

Cite this

Zhou, L. T., Liu, D., Kang, H. C., Lu, L., Huang, H. Z., Ai, W. Q., Zhou, Y., Deng, M. F., Li, H., Liu, Z. Q., Zhang, W. F., Hu, Y. Z., Han, Z. T., Zhang, H. H., Jia, J. J., Sarkar, A. K., Sharaydeh, S., Wang, J., Man, H. Y., ... Zhu, L. Q. (2023). Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease. Science Advances, 9(16), eabq7105. Article eabq7105. https://doi.org/10.1126/sciadv.abq7105

@article{c87e03b397c5486fb6bd60fcfcda2990,

title = "Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer{\textquoteright}s disease",

abstract = "The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyper-phosphorylated tau, a pathological hallmark in Alzheimer{\textquoteright}s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.",

author = "Zhou, \{Lan Ting\} and Dan Liu and Kang, \{Hui Cong\} and Lu Lu and Huang, \{He Zhou\} and Ai, \{Wen Qing\} and Yang Zhou and Deng, \{Man Fei\} and Hao Li and Liu, \{Zhi Qiang\} and Zhang, \{Wei Feng\} and Hu, \{Ya Zhuo\} and Han, \{Zhi Tao\} and Zhang, \{Hong Hong\} and Jia, \{Jian Jun\} and Sarkar, \{Avijite Kumer\} and Saldin Sharaydeh and Jie Wang and Man, \{Heng Ye\} and Marcel Schilling and Lars Bertram and Youming Lu and Ziyuan Guo and Zhu, \{Ling Qiang\}",

note = "Funding Information: Acknowledgments:TheAK OmicewereagiftfromJ.SchnermannatNIDDK/NIH.W ethankall thetechniciansandcorefacilityintheAnalyticalandT es tingCenter,HuazhongUniversityof ScienceandT echnology .Funding:ThisstudywaspartiallysupportedbytheNationalKey ResearchandDevelopmentProgramofChina(grantno.2019YFE0121200),theNationalNatural ScienceFoundationofChina(grantnos.82030032,82261138555,32070960,81761138043, 81901103,31721002,and81961128005),theTop-NotchYoungTalentsProgramofChinaof 2014,theAcademicFrontierYouthT eam ofHuazhongUniversityofScienceandT echnology to L.-Q.Z.,theHubeiProvincialNaturalScienceFoundation(2022CFA004toL.-Q.Z.),theNIH(grant no. NS122169), the Cincinnati Children{\textquoteright}s Hospital Medical Center (CCHMC) Trustee Grant A ward,andtheCCHMCCenterforPediatricGenomicsA wardtoZ.G.Authorcontributions:L.-Q.Z.initiatedanddesignedthestudy.L.-Q.Z.andD.L.supervisedthestudy.L.-T .Z., H.-C.K.,H.-Z.H.,W .-Q.A., Y .Z., andW .-F .Z. performedthemolecularbiologicalexperimentsandanimal experiments.L.-T .Z. andZ.-Q.L.analyzedtheRNA-seqdata.M.-F .D., H.L.,andL.-T .Z. performed the electrophysiological recordings. L.L., A.K.S., S.S., M.S., and Z.G. generated AD iPSC lines, performedbiochemicalandelectrophysiologicalexperimentsusingiPSCs,andanalyzedthe data.Y .-Z.H., Z.-T .H., H.-H.Z.,andJ.-J.J.providedthehumantissuesamples.L.B.andM.S. analyzedtheexpressionofMEF2candADORA1inhumansamples.L.-T .Z., H.-C.K.,Y .L., D.L.,J.W ., H.-Y .M., andL.-Q.Z.analyzedthedata.L.-Q.Z.,L.-T .Z., D.L.,andZ.G.wrotethemanuscript. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:TheRNA-seqdataareaccessiblethroughGEOSeriesaccessionnumber GSE193826(www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193826).Alldataneededto evaluatetheconclusionsinthepaperarepresentinthepaperand/ortheSupplementary Materials. Funding Information: This study was partially supported by the National Key Research and Development Program of China (grant no. 2019YFE0121200), the National Natural Science Foundation of China (grant nos. 82030032, 82261138555, 32070960, 81761138043, 81901103, 31721002, and 81961128005), the Top-Notch Young Talents Program of China of 2014, the Academic Frontier Youth Team of Huazhong University of Science and Technology to L.-Q.Z., the Hubei Provincial Natural Science Foundation (2022CFA004 to L.-Q.Z.), the NIH (grant no. NS122169), the Cincinnati Children{\textquoteright}s Hospital Medical Center (CCHMC) Trustee Grant Award, and the CCHMC Center for Pediatric Genomics Award to Z.G. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = apr,

day = "21",

doi = "10.1126/sciadv.abq7105",

language = "English",

volume = "9",

pages = "eabq7105",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "16",

}

Zhou, LT, Liu, D, Kang, HC, Lu, L, Huang, HZ, Ai, WQ, Zhou, Y, Deng, MF, Li, H, Liu, ZQ, Zhang, WF, Hu, YZ, Han, ZT, Zhang, HH, Jia, JJ, Sarkar, AK, Sharaydeh, S, Wang, J, Man, HY, Schilling, M, Bertram, L, Lu, Y, Guo, Z & Zhu, LQ 2023, 'Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease', Science Advances, vol. 9, no. 16, eabq7105, pp. eabq7105. https://doi.org/10.1126/sciadv.abq7105

TY - JOUR

T1 - Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease

AU - Zhou, Lan Ting

AU - Liu, Dan

AU - Kang, Hui Cong

AU - Lu, Lu

AU - Huang, He Zhou

AU - Ai, Wen Qing

AU - Zhou, Yang

AU - Deng, Man Fei

AU - Li, Hao

AU - Liu, Zhi Qiang

AU - Zhang, Wei Feng

AU - Hu, Ya Zhuo

AU - Han, Zhi Tao

AU - Zhang, Hong Hong

AU - Jia, Jian Jun

AU - Sarkar, Avijite Kumer

AU - Sharaydeh, Saldin

AU - Wang, Jie

AU - Man, Heng Ye

AU - Schilling, Marcel

AU - Bertram, Lars

AU - Lu, Youming

AU - Guo, Ziyuan

AU - Zhu, Ling Qiang

N1 - Funding Information: Acknowledgments:TheAK OmicewereagiftfromJ.SchnermannatNIDDK/NIH.W ethankall thetechniciansandcorefacilityintheAnalyticalandT es tingCenter,HuazhongUniversityof ScienceandT echnology .Funding:ThisstudywaspartiallysupportedbytheNationalKey ResearchandDevelopmentProgramofChina(grantno.2019YFE0121200),theNationalNatural ScienceFoundationofChina(grantnos.82030032,82261138555,32070960,81761138043, 81901103,31721002,and81961128005),theTop-NotchYoungTalentsProgramofChinaof 2014,theAcademicFrontierYouthT eam ofHuazhongUniversityofScienceandT echnology to L.-Q.Z.,theHubeiProvincialNaturalScienceFoundation(2022CFA004toL.-Q.Z.),theNIH(grant no. NS122169), the Cincinnati Children’s Hospital Medical Center (CCHMC) Trustee Grant A ward,andtheCCHMCCenterforPediatricGenomicsA wardtoZ.G.Authorcontributions:L.-Q.Z.initiatedanddesignedthestudy.L.-Q.Z.andD.L.supervisedthestudy.L.-T .Z., H.-C.K.,H.-Z.H.,W .-Q.A., Y .Z., andW .-F .Z. performedthemolecularbiologicalexperimentsandanimal experiments.L.-T .Z. andZ.-Q.L.analyzedtheRNA-seqdata.M.-F .D., H.L.,andL.-T .Z. performed the electrophysiological recordings. L.L., A.K.S., S.S., M.S., and Z.G. generated AD iPSC lines, performedbiochemicalandelectrophysiologicalexperimentsusingiPSCs,andanalyzedthe data.Y .-Z.H., Z.-T .H., H.-H.Z.,andJ.-J.J.providedthehumantissuesamples.L.B.andM.S. analyzedtheexpressionofMEF2candADORA1inhumansamples.L.-T .Z., H.-C.K.,Y .L., D.L.,J.W ., H.-Y .M., andL.-Q.Z.analyzedthedata.L.-Q.Z.,L.-T .Z., D.L.,andZ.G.wrotethemanuscript. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:TheRNA-seqdataareaccessiblethroughGEOSeriesaccessionnumber GSE193826(www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193826).Alldataneededto evaluatetheconclusionsinthepaperarepresentinthepaperand/ortheSupplementary Materials. Funding Information: This study was partially supported by the National Key Research and Development Program of China (grant no. 2019YFE0121200), the National Natural Science Foundation of China (grant nos. 82030032, 82261138555, 32070960, 81761138043, 81901103, 31721002, and 81961128005), the Top-Notch Young Talents Program of China of 2014, the Academic Frontier Youth Team of Huazhong University of Science and Technology to L.-Q.Z., the Hubei Provincial Natural Science Foundation (2022CFA004 to L.-Q.Z.), the NIH (grant no. NS122169), the Cincinnati Children’s Hospital Medical Center (CCHMC) Trustee Grant Award, and the CCHMC Center for Pediatric Genomics Award to Z.G. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved.

PY - 2023/4/21

Y1 - 2023/4/21

N2 - The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyper-phosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

AB - The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyper-phosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

UR - https://www.scopus.com/pages/publications/85153540200

UR - https://www.mendeley.com/catalogue/91aa1bbe-8d45-3419-8efb-b155cf97cf1e/

U2 - 10.1126/sciadv.abq7105

DO - 10.1126/sciadv.abq7105

M3 - Journal articles

C2 - 37083538

AN - SCOPUS:85153540200

SN - 2375-2548

VL - 9

SP - eabq7105

JO - Science Advances

JF - Science Advances

IS - 16

M1 - eabq7105

ER -

Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this