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 dis-eases. 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 3xTg 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. Rebuild-ing 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 neu-ronal 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.

Automated summary

In this study, it was found that excessive expression of adenosine receptor 1 (A1R) in neurons is dependent on tau pathology and regulated posttranscriptionally by Mef2c via miR-133a-3p. Restoring the miR-133a-3p/A1R signal effectively improved synaptic and memory impairments in Alzheimer's disease (AD) mice. Additionally, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. These findings demonstrate the remodeling of neuron-glial cross-talk by tau pathology and suggest A1R as a potential therapeutic target for AD.