On April 21,2023, Professor ZHU Lingqiang 's team of Huazhong University of Science and Technology published an article entitled " Tau pathology is epigenetically remodels the neuron-glial cross-talk in Alzheimer 's disease " in Science Advances. It was found that pathological Tau protein regulates the neuron-astrocyte cross-talk by affecting the neuron A1R / Lcn2 pathway. It is involved in AD cognitive impairment and synaptic damage, providing a new target for AD treatment.

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.

ZHOU Lanting, Ph.D., 2017, Department of Pathophysiology, School of Basic Medical Sciences, Huazhong University of Science and Technology; Professor LIU Dan, Department of Medical Genetics; Director KANG Huicong, Department of Neurology, Tongji Hospital; and Professor ZHU Lingqiang, Department of Neurology, Tongji Hospital; and Professor LU Youming, Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, were the co-first authors, and Professor ZHU Lingqiang, Department of Neurology, Tongji Hospital; and Professor LU Youming, Department of Neurology, Tongji Hospital, Tongji Hospital, Tongji Hospital; were the co-communicating authors.

Paper link: http://doi.org/10.1126/sciadv.abq7105