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


    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 languageEnglish
    Article numbereabq7105
    JournalScience Advances
    Issue number16
    Pages (from-to)eabq7105
    Publication statusPublished - 21.04.2023

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