权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting emerging P2RX7 signaling pathways in animal models of Alzheimer's disease

针对阿尔茨海默病动物模型中新兴的 P2RX7 信号通路

基本信息

批准号：
10573168
负责人：
Tsuneya Ikezu
金额：
$ 39.13万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573168
关键词：
Acceleration Age Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Anatomy Animal Model Astrocytes Brain Brain Diseases Brain region Cations Cell model Cells Clinical Complex Cre driver Data Dependovirus Development Disease Endosomes Enzyme-Linked Immunosorbent Assay Genetic Goals Hippocampus In Vitro Incubated Inflammatory LoxP-flanked allele Maps Mediating Microglia Molecular Mus Neurofibrillary Tangles Neuroglia Neurons Pathologic Pathology Pattern Phagocytosis Prevention Process Proteins Purinoceptor Series Signal Pathway Sorting Source Specificity Symptoms System TSG101 gene Tauopathies Testing Therapeutic behavior test behavioral phenotyping cell type comparison control exosome experimental study extracellular vesicles feeding hippocampal pyramidal neuron hyperphosphorylated tau in vivo in vivo Model inhibitor microvesicles mouse model multi-electrode arrays neuropathology neurotoxicity novel pharmacologic prevent protein aggregation tau Proteins tau aggregation tau expression tau mutation trafficking uptake

项目摘要

Neurofibrillary tangles, composed of intracellular aggregates of hyperphosphorylated tau protein are by far the most correlated pathology with clinical symptoms of Alzheimer disease (AD). Emerging evidence suggests that extracellular vesicles (EVs), such as exosomes and microvesicles, transfer pathological tau protein between cells as vehicles, and propagate tau pathology in different brain regions. It is urgently important to find the molecular basis of brain-derived EV, which critically regulates the transport and uptake of pathogenic tau protein between neuronal cells and aggregation of tau protein in recipient neurons. The purpose of the current application is to delineate the effect of P2RX7, a purinergic receptor, on EV- mediated tau propagation. Our preliminary data have shown that suppressing microglial EV secretion by GSK 1482160 compound, a specific inhibitor of the P2RX7, dramatically reduces tau aggregation in CA1 and CA3 pyramidal neuronal cells and dentate granular cells with P301S tauopathy animal model. Interestingly this coalesces with reduction of exosome-specific ‘endosomal sorting complexes required for transport’ (ESCRT) EV marker, TSG101, in the same hippocampal regions, suggesting the possible EV trafficking from microglia to hippocampal neurons, which may transfer and seeds misfolded tau and accelerate protein aggregation in receiving neurons. Thus, those data indicate the regulatory mechanism by P2RX7 on EV mediated tau propagation and posit the therapeutic potential of the P2RX7 inhibitor for AD or other tauopathy. We hypothesize that P2RX7 critically regulates the transfer of EVs between microglia and neurons in the hippocampal neurons, thereby facilitate spreading misfolded tau. We will validate the effect of GSK1482160 on tau propagation by recapitulating those findings using P2rx7 deletion in P301S tau mice and adeno-associated virus (AAV)-based tau propagation mouse model. In Aim 1, we will determine the effect of systemic deletion of P2rx7 in P301S mouse. The distribution of EV markers and tau pathology in the hippocampal regions will be evaluated and compared with the findings from GSK1482160-administered P301S mice. In Aim 2, we will determine the effect of P2RX7 on secretion and transfer of EV and EV-associated tau and its aggregation potency in vitro. This will determine which cell type is particularly responsible for P2RX7 regulated tau spread into hippocampal neurons. In Aim 3, we will confirm the cell type, which is selected in Aim 2, for the export of EVs into hippocampal neurons by cell type- specific deletion of P2rx7 or Tsg101, an exosome synthesis molecule, and validate if P2RX7-mediated EV secretion are responsible for tau propagation using AAV-based tau propagation mouse model. Successful completion of this study will enhance our understanding of molecules that mediates secretion of EVs from glia to neurons in vitro and in vivo, and identify novel targets for AD.

神经纤维缠结是由细胞内过度磷酸化的tau蛋白聚集体组成的