Brain for the first time!

Authors ︱ Zhang Yalun, Song Youqiang in charge of editors ︱ Wang Sizhen Alzheimer's disease (Alzheimer's disease, referred to as AD), also known as Alzheimer's disease, is a progressively developing neurodegenerative disease
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Neurofibrillary tangles (NFT) formed by β-amyloid (Aβ) plaques and hyperphosphorylated tau protein are two hallmark pathological features of AD [1, 2]
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Studies in the past ten years have shown that Aβ is related to the function of tau.
Soluble Aβ and tau can work together, independent of the plaques and tangles they accumulate, leading to healthy neurons entering a disease state, and neurons will undergo cell cycle regeneration.
Phenomena such as entry and synaptic disorders [3-5]
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Aβ may be located upstream of tau in the pathogenesis of AD, leading to the accumulation of toxic tau [3-5]
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Aβ-induced cell cycle re-entry will lead to the initiation of some protein kinases that phosphorylate tau, such as fyn, PKA and CaMKII [6]
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However, the molecular pathway that connects Aβ and tau is still unclear [3-5]
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 On August 25, 2021, Youqiang Song's research team from the State Key Laboratory of Brain and Cognitive Sciences at the University of Hong Kong School of Medicine published an online research paper entitled "Amyloid β toxicity modulates tau phosphorylation through the PAX6 signalling pathway" in Brain magazine, the first time The important role of Pax6 gene in the pathogenesis of AD is explained.
Pax6 is a potential molecular "bridge" connecting Aβ and tau
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Zhang Yalun and Zhang Yi are the co-first authors of the paper, and Song Youqiang is the corresponding author
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Researchers found that Pax6, an important transcription factor in neural development [7], is expressed elevated in AD mouse models and patient brains
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In AD neuronal models, down-regulation of Pax6 expression can reduce Aβ-induced neuronal death, and Pax6 helps mediate the effect of Aβ on tau phosphorylation
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Therefore, this study reveals new potential therapeutic targets for AD
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 A number of related studies in vitro and in vivo suggest that in the AD brain, cyclin may be a key regulator of neuronal dysfunction and loss [8, 9]
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Cell cycle dysregulation is involved in the death of AD neurons.
Cyclin-dependent kinases/retinoblastoma protein/transcription factor E2F1, that is, the CDK/pRB/E2F1 signaling pathway may play a major role, and Aβ Activation of CDK4/6 leads to phosphorylation of pRB and activation of E2F1 [9-11]
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 Therefore, the researchers first performed an array-based gene expression and gene function enrichment analysis to determine the downstream events of the signaling pathway
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It is found that among the many potential regulatory target genes of E2F1, the gene PAX6 has the strongest correlation with E2F1, and its expression is up-regulated in the human AD brain
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Pax6 is a transcription factor that plays an important role in the development of the nervous system such as the eyes, brain, and olfactory bulb [12-13]
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So, immediately, the researchers checked the expression level of Pax6 in the frontal cortex of 14 control brains from the Canadian Brain Tissue Bank and 14 brains of patients affected by AD.
Compared with control brains, the Pax6 protein in AD brains Up-regulation of expression level (Figure 1 A, B)
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In order to further confirm this observation in the in vivo AD model, the researchers used TgCRND8 mice as the animal model, which exhibited early Aβ deposition and memory impairment [14]
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The researchers found that since TgCRND8 mice were 4 months old, the proportion of neurons expressing Pax6 in the entorhinal cortex increased significantly, and this change continued throughout the disease stage (Figure 1 C, D)
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Figure 1 Pax6 expression is significantly increased in the brains of Alzheimer's patients (A, B) and the entorhinal cortex of TgCRND8 mice (B, C) (Image source: Song Youqiang laboratory) Next, the researchers performed the microarray data A centralized comparison of 176 brain samples from AD patients and 187 brain samples from control human brains found that, based on the results of chromatin immunoprecipitation (ChIP) sequencing data, Pax6 showed a high correlation with E2F1 function
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As a transcription factor, E2F1 plays a key role in cell cycle regulation.
It can regulate the transformation of G1/S process and DNA repair in the cell cycle [15]
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 To further confirm this, the authors identified several binding sites for E2F1 and c-Myb in the promoter region of the Pax6 gene
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The transcription factor c-Myb is a downstream gene regulated by E2F1 in the cell cycle [16]
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The results of ChIP experiments in mouse cortical neurons and human cell lines showed that E2F1 and c-Myb can bind to the Pax6 promoter
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Further results indicate that Pax6 is the direct target of E2F1 and its downstream target c-Myb
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Silencing of E2F1 by siRNA reduced Aβ-induced overexpression of Pax6 and c-Myb, indicating that E2F1 is responsible for their upregulation
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Importantly, the down-regulation of c-Myb or Pax6 protects neurons from death caused by Aβ, indicating that Pax6 and c-Myb are necessary downstream mediators of the E2F1 signaling pathway
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 Finally, the researchers performed a whole-gene expression analysis to determine the downstream target of Pax6
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The RNA sequence results show that Pax6 regulates the transcription of GSK-3β
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GSK-3β is a kinase involved in the formation of tau hyperphosphorylation and neurofibrillary tangles (NFT) [17]
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Down-regulation of Pax6 reduced the phosphorylation levels of Ser356, Ser396 and Ser404 of tau protein through GSK-3β
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Figure 2 The possible role model of Pax6 in β-amyloid-induced neurotoxicity (picture quoted from: Y.
Zhang et al.
, Brain.
2021; awab134) Conclusion and discussion of the article, inspiration and outlook The research provides a mechanism (Figure 2) Through this mechanism, Aβ neurotoxicity leads to tau hyperphosphorylation through cell cycle activation and subsequent c-Myb/Pax6/GSK-3β activation
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This signal cascade contains several potential targets for drug intervention
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Therefore, our discovery adds to the molecular mechanism that connects Aβ and tau, and points the direction for the goal of drug discovery
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 In addition, this study also suggests the possibility of early diagnosis and therapeutic intervention for AD.
It is best to intervene before the occurrence of Aβ plaque formation and neurofibrillary tangles (NFT) composed of abnormal phosphorylated tau protein in the brain
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 This research also needs follow-up answers to some questions.
For example, we found that there are other AD-related targets downstream of Pax6.
Whether there are other mechanisms to regulate the phosphorylation of Tau protein requires further experimental proof
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 At present, we have several patented drug candidates that can be reused to inhibit Pax6 signaling pathway to treat AD
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The use of these candidate drugs to treat AD mouse models in our preliminary results shows that these drugs can significantly improve the learning and memory of AD mouse models, which will open up another way for us to combat this disease
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We will conduct clinical trials in the future
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Original link: https://doi.
org/10.
1093/brain/awab134 Left: Zhang Yalun (first author); Right: Zhang Zhi (first from left, co-first author): Professor Jin Dongyan (second from left), Dr.
Song Youqiang (Second from right, corresponding author), Dana SM Wong (first from right), Yue Ming (first from right, back row), Li Siwen (second from right, back row) (photo source: Song Youqiang Laboratory) The research team of Dr.
Song Youqiang from the College and the State Key Laboratory of Brain and Cognitive Science, including former students Dr.
Yalun Zhang, Cheung Toa Ng, Mr.
Zhou Yongxuan, Jia Yizhen, and Zhang Zhigang; current students: Zhang Zhi, Yue Ming, Li Siwen; and Hong Kong Professor Jin Dongyan and Ms.
Dana SM Wong and Dr.
Zhao Jian from the Department of Ophthalmology at the University’s School of Biomedicine
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 The research is in collaboration with the Tanz Neurodegenerative Disease Research Center of the University of Toronto, including Dr.
Christopher Bohm, Dr.
Jennifer Griffin, Prof.
Ekaterina Rogaeva, Prof.
Paul E.
Fraser and Prof.
Peter St George-Hyslop, also from the University of Cambridge
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Other contributors include: Yuan Qiuju, School of Traditional Chinese Medicine, The Chinese University of Hong Kong; Professor Wang Binbin, National Family Planning Research Institute, Beijing, China; Dr.
Yahyah Aman and Professor Evandro F.
Fang from the Department of Clinical Molecular Biology, University of Oslo
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Selected articles from previous issues [1] JAMA Neurol︱ Attention! Young people are more likely to suffer from "Alzheimer's disease"? [2] Sci Adv︱ Heavyweight! DNA methylation protein DNMT1 mutation can induce neurodegenerative diseases [3] Cell︱ new discovery! New enlightenment of midbrain-regulated movement phenomenon for the treatment of Parkinson’s disease [4] Cereb Cortex︱MET tyrosine kinase signal transduction timing abnormality is a key mechanism affecting the development and behavior of normal cortical neural circuits in mice [5] Nat Biomed Eng︱ The team of academician Ye Yuru develops a new strategy for whole-brain gene editing-mediated treatment of Alzheimer’s disease [6] Luo Liqun Science's heavy review System interpretation ︱ Neural circuit structure-a system that makes the brain "computer" run at high speed [7] Sci Adv ︱Important discovery! The calcium homeostasis regulatory protein Calhm2 regulates the activation of microglia and participates in the process of Alzheimer's disease [8] EMBO J︱ new discovery! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability [9] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal the molecular mechanism of SUMO modification regulating neurogenesis in adult mice [10] Cereb Cortex︱A2A receptor antagonist can Reversing sequence learning impairments induced by abnormal aggregation of α-Syn References (slide up and down to view) 【1】Canter RG, Penney J, Tsai LH.
The road to restoring neural circuits for the treatment of Alzheimer's disease.
Nature 2016; 539(7628) ): 187-96.
[2] Edwards FA.
A Unifying Hypothesis for Alzheimer's Disease: From Plaques to Neurodegeneration.
Trends Neurosci 2019; 42(5): 310-22.
[3] Bloom GS.
Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis.
JAMA Neurol 2014;