【2023 學術演講】Monocyte activation and neurotoxicity of hyperphosphorylated  tau oligomers

2023 神醫中心學術演講7  (實體+線上) 

日期 : 9月 26日星期二

時間 : 上午11:00  

地點 : 國衛院竹南院區/ 行政大樓B1第6會議室

主題 : Monocyte activation and neurotoxicity of hyperphosphorylated  tau oligomers

講師 : Hong-Ru Chen ( 陳虹如),   Ph.D.
Assistant Professor , Department of Life Sciences and Institute of Genome Sciences  National Yang Ming Chiao Tung University

報名連結

摘要

Phosphorylation is a normal post-translational modification of tau, but hyperphosphorylation may provoke tau aggregation into insoluble paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), a defining pathological feature of Alzheimer’s diseases (AD). Recent studies suggested that pre-fibrillary, phosphorylated tau oligomers may already possess neurotoxicity, since an early rise of soluble phosphorylated tau oligomers in the cerebrospinal fluid is detected in AD patients, long before the onset of cognitive impairments. Past studies of the neurotoxicity of tau oligomers mainly relied on in-vitro heparin-induced non-phosphorylated tau fibrils or the p-tau fibrils that were isolated from the AD patient’s brains. However, heparin-induced tau fibrils showed minimal neurotoxicity, while the p-tau fibrils isolated from the AD patient brains may not represent the effects of soluble p-tau oligomers. To fill the missing gap, we have investigated the effects of soluble hyperphosphorylated tau using the PIMAX system. We found that recombinant p-tau induces neurite retraction, mitochondrial SO emission, condensation of the mitochondria, and finally neuronal death in a dose-dependent manner, whereas non-phosphorylated tau lacks these effects. Next, we used stereotaxic injection to compare the effects of non-phosphorylated tau and p-tau in mouse brains. We found that intra-hippocampal injection of p-tau induced the progression of MC1-positive conformational changes of p-tau from dorsal hippocampus to the cingulate cortex, anxiety behaviors, and TUNEL-positive neuronal death, as well as, monocytes infiltration along with OPC and myelin disruption. Infiltrating monocytes in the brain parenchyma expressed high levels of Trem2, proinflammatory cytokines and clustered at the myelin sheath after intrahippocampal p-tau injection. In conclusion, our results support substantial neurotoxicity of soluble hyperphosphorylated tau oligomers, and suggest a novel system to study the underlying mechanisms and potential protective treatments.

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