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Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease
Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease
- Source :
- Science Advances. 9
- Publication Year :
- 2023
- Publisher :
- American Association for the Advancement of Science (AAAS), 2023.
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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 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.
- Subjects :
- Multidisciplinary
Subjects
Details
- ISSN :
- 23752548
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi...........ac23785ce36d9410b06d65db463b3ad7
- Full Text :
- https://doi.org/10.1126/sciadv.abq7105