Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.
Lan-Ting ZhouDan LiuHui-Cong KangLu LuHe-Zhou HuangWen-Qing AiYang ZhouMan-Fei DengHao LiZhi-Qiang LiuWei-Feng ZhangYa-Zhuo HuZhi-Tao HanHong-Hong ZhangJian-Jun JiaAvijite Kumer SarkarSaldin SharaydehJie WangHeng-Ye ManMarcel SchillingLars BertramYouming LuZiyuan GuoLing-Qiang ZhuPublished in: Science advances (2023)
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.
Keyphrases
- high fat diet induced
- signaling pathway
- cerebrospinal fluid
- spinal cord
- cerebral ischemia
- working memory
- cognitive decline
- gene expression
- epithelial mesenchymal transition
- adipose tissue
- insulin resistance
- mild cognitive impairment
- pi k akt
- neuropathic pain
- drug delivery
- spinal cord injury
- genome wide
- blood brain barrier
- cell proliferation