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

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 hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), re...

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Published in:Science advances 2023-04, Vol.9 (16), p.eabq7105-eabq7105
Main Authors: Zhou, Lan-Ting, Liu, Dan, Kang, Hui-Cong, Lu, Lu, Huang, He-Zhou, Ai, Wen-Qing, Zhou, Yang, Deng, Man-Fei, Li, Hao, Liu, Zhi-Qiang, Zhang, Wei-Feng, Hu, Ya-Zhuo, Han, Zhi-Tao, Zhang, Hong-Hong, Jia, Jian-Jun, Sarkar, Avijite Kumer, Sharaydeh, Saldin, Wang, Jie, Man, Heng-Ye, Schilling, Marcel, Bertram, Lars, Lu, Youming, Guo, Ziyuan, Zhu, Ling-Qiang
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Animals
Astrocytes - metabolism
Cellular Neuroscience
Disease Models, Animal
Humans
Mice
Mice, Transgenic
MicroRNAs - metabolism
Neurons - metabolism
Neuroscience
SciAdv r-articles
tau Proteins - genetics
tau Proteins - metabolism
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Summary: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 hyperphosphorylated 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abq7105