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The team of Professor Kong Wei/Professor Wu Hui, National Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, has made new progress
in the field of Alzheimer's pathogenesis 。 The study has been published in the Journal
of Neuroinflammation today under the title "Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer's disease.
Alzheimer's disease (AD) is the world's most widespread and most common chronic developing neurodegenerative disease
in older adults.
The clinical manifestations are a deterioration of cognitive and memory functions, and a slow decline
in the ability to perform daily living.
However, the current treatment methods can only improve the symptoms of AD patients and cannot fundamentally block the disease process, so elucidating the pathogenesis of AD is of great significance
for drug development.
Neurofibrillary tangles (NFTs) are one of the main pathological features of AD and consist of
hyperphosphorylated tau proteins.
Overphosphorylated tau protein can disrupt the stability of microtubules, affect axon transport and damage neurons, but the specific mechanism by which phosphorylated tau leads to neuronal death needs to be further elucidated
Previous studies have shown that RIPK1, a key factor in the regulation of programmed necrosis in the brain of AD patients, is significantly upregulated and MLKL dimerization is increased, but how programmed necrosis in AD brain is triggered and the related regulatory mechanism is not clear
Therefore, the research team first confirmed that phosphorylated tau protein can upregulate RIPK1, RIPK3 and MLKL in mouse hippocampal neurons HT22 and human neuroblastoma SY-SY5Y, promote the formation of necrosomes and thus trigger programmed necrosis
Next, transcriptome sequencing results showed that there was significant upregulation of inflammatory factors during phosphorylated tau-induced necrosis, and CRISPR-Cas9 knockout experiments showed that the inflammatory response was mediated
by the RIPK1-RIPK3-MLKL axis.
Further studies have found that the NF-κB signaling pathway responds to the activation of the RIPK1-RIPK3-MLKL axis and thus promotes the transcription
of multiple inflammatory factors.
In vivo experiments also confirmed that the treatment of Nec-1s, an inhibitor of RIPK1, in AD model mice inhibited the occurrence of programmed necrosis and the activation of microglia, and alleviated memory and cognitive impairment
in model mice.
The first thesis was completed by Jilin University, and the first author was Dong Yue
, a graduate student from the College of Life Sciences, Jilin University.
Professor Kong Wei and Professor Wu Hui of the National Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, are the co-corresponding authors
of the paper.
This research work was supported
by the National Natural Science Foundation of China and the Natural Science Foundation of Jilin Province.
Full text link: https://doi.