Transcriptional Signatures of Tau and Amyloid Neuropathology
Transcriptional Signatures of Tau and Amyloid Neuropathology
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DOI：
10.1016/j.celrep.2020.01.063
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发表时间：
2020-02-11
期刊：
影响因子：
8.8
通讯作者：
Mill, Jonathan
中科院分区：
文献类型：
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作者：
Castanho, Isabel;Murray, Tracey K.;Mill, Jonathan
阿尔茨海默病（AD）与过度磷酸化的tau蛋白的细胞内聚集和β-淀粉样蛋白在新皮质中的积累有关。我们使用携带人类tau蛋白（rTg 4510）和淀粉样蛋白前体蛋白（J20）突变的转基因小鼠来研究与tau蛋白和淀粉样蛋白病理学进展相关的转录变化。rTg 4510小鼠的特征在于内嗅皮层中广泛的转录差异，其变化与跨多个脑区域的神经病理学负荷平行。差异表达的转录本与家族性和散发性AD的遗传学研究中鉴定的基因重叠。系统级分析鉴定了与tau的进行性积累相关的离散共表达网络，其富集了先前在AD病理学中涉及的基因和途径，并且与在人类AD皮质中鉴定的共表达网络重叠。我们的数据为tau蛋白积累中的免疫应答成分提供了进一步的证据，并揭示了与AD神经病理学进展相关的分子途径。
Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of b-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.