Front Aging Neurosci︱PTAFR as a Novel Biomarker for Alzheimer's Diagnosis and Treatment

Written by Liu Junxiu, edited by Liu Mingyan, plate made by Wang Sizhen, Zha Jiaxue Alzheimer's Disease (AD), as an age-related neurodegenerative disease, seriously endangers the life of the elderly[1,
Clinically AD patients are mostly manifested as cognitive deficits, memory loss and language dysfunction [
At this stage, the recognized hallmark pathophysiological changes of AD include senile plaques formed by the deposition of amyloid-beta (Aβ) in the brain, neurofibrillary tangles caused by hyperphosphorylation of tau protein, and extensive neuronal loss and glial Mass proliferation of cells [4,
However, changes in AD pathology often precede the onset of clinical sympto.
When clinical symptoms appear, AD progression is difficult to reverse [6,
Therefore, early diagnosis and treatment are the keys to delaying AD progressi.
Currently, the diagnosis of AD mainly relies on the MMSE score, 18 FDG-PET, CT or MRI scans, and the identification of biomarkers such as T-tau, p-tau, and Aβ42 in cerebrospinal flu.
However, these methods suffer from high cost, lack of specificity, or invasive sample collection [
Therefore, finding identifiable and highly specific potential AD biomarkers has become an urgent probl.
 On April 28, 2022, Liu Mingyan's team from the Department of Pharmacology, School of Pharmacy, China Medical University published a paper entitled "Platelet Activating Factor Receptor Exaggerates Microglia-Mediated Microenvironment by IL10-STAT3 Signaling: A Novel Potential Biomarker and Target for Frontiers in aging neuroscien.
Diagnosis and Treatment of Alzheimer's Disease" research pap.
.
Liu Junxiu is the first author of the paper, and Professor Liu Mingyan is the first corresponding author of the pap.
Through GEO chip analysis, the authors found that PTAFR, a biomarker for early diagnosis of AD, was significantly up-regulated in brain tissue, peripheral blood and cerebrospinal fluid in the early stage of AD, and revealed that PTAFR inhibits IL10-STAT3 signaling in microgl.
Molecular mechanisms of worsening neuronal inflammatory microenvironment and promoting AD developme.
Platelet activating factor receptor (PTAFR) plays an important role in many diseas.
Studies have reported that PTAFR can be used as an important target of breast cancer bone metastasis [9]; promote the formation of fibrosis after myocardial infarction [10]; aggravate renal injury caused by renal tubular inflammatory response [1
However, PTAFR is rarely reported in the field of neurology, whether it can be used as a biomarker for the early diagnosis of AD, and its specific pathogenic mechanism in AD progression is still unkno.
 First, in order to obtain the differentially expressed genes related to AD progression, the authors used GEO data to analyze the differentially expressed genes (DEGs) in different stages of AD and found that a total of 32 DEGs were significantly differentially expressed in different stages of AD, of which 25 genes were significantly differentially expressed in .

All stages showed significantly high expression (Figure 1), which was in line with the characteristics of screening biomarke.

Subsequently, the authors performed enrichment analysis on DEGs and found that they were closely related to biological pathways including inflammatory responses; Cytoscape software assessed the interaction between DEGs and found that 22 genes including PTAFR were associated with AD core There is a certain interaction between the disease gene APP (Figure
 Figure 1 DEGs in the hippocampus of AD patients (source: Junxiu Liu, et .

, Front Aging Neurosci, 2022) Figure 2 Enrichment and PPI network analysis of DEGs in the hippocampus of AD patients (source: Junxiu Liu, et .

, Front Aging Neurosci, 2022) Further, in order to screen potential biomarkers for the diagnosis of AD, the authors conducted an intersection analysis of 32 DEGs in the hippocampal brain region at various stages of AD and DEGs in the cerebrospinal fluid and blood of AD patients, and obtained two At the same time, potential target genes PTAFR and AKAP13 were up-regulated in the blood, cerebrospinal fluid and hippocampus of AD patients (F.

3.

By comparing the correlations of the two genes with the MMSE score, Braak score, and neurofibrillary tangles score, respectively, it was found that PTAFR showed a stronger correlation with the above scores than AKAP13 (Figure 3B-.

In addition, the authors found that PTAFR was also highly expressed in the entorhinal cortex, hippocampus, and temporal cortex of AD patients (F.

3H), and TAFR had a significantly higher expression characteristic in microglia than other central nervous system cells (F.

3.

), suggesting that PTAFR is more beneficial as an AD biomarker for further in-depth pathogenesis resear.
 Figure 3 PTAFR is specifically highly expressed in peripheral blood, cerebrospinal fluid and hippocampus of AD patien.

(Image source: Junxiu Liu, et .

, Front Aging Neurosci, 2022) Then, based on the above findings, the authors carried out verifications at the in vivo and in vitro leve.

The results showed that the expression of PTAFR was significantly up-regulated in the brain and peripheral blood of APP/PS1 mice, and the expression of PTAFR was significantly increased in the LPS+Aβ-induced BV2 cell line (Figure 4), compared with other AD model cel.

Lineages such as neurons and astrocytes were not significantly differe.

This indicates that PTAFR is significantly elevated in AD brain and peripheral blood, suitable to be a biomarker for early diagnosis of AD, and its specific high expression in microglia shows the same results as predicted, suggesting that it is related to Microglia-mediated neuroinflammatory responses are closely relat.

 F.

4 PTAFR is highly expressed in APP/PS1 mice and LPS+Aβ-induced BV2 cells (Source: Junxiu Liu, et .

, Front Aging Neurosci, 202
Studies have reported that PTAFR is associated with renal injury [11, 12] and The secretion of inflammatory factors is closely related to retinal neovascularization [13], suggesting that microglia-mediated neuroinflammation may be a factor in the involvement of PTAFR in AD progressi.

Through the STRING online tool, the authors found that PTAFR is closely related to the inflammatory factors IL-10 and STATTherefore, it was hypothesized that PTAFR activates microglia-mediated neuroinflammation through the IL10-STAT3 signaling pathway, thereby aggravating the inflammatory damage of AD neuro.
The authors found that in BV2 cells treated with LPS+Aβ, the mRNA and protein levels of IL-10 were significantly decreased, while the levels of STAT3 and IL-6 were significantly increased, and the conditioned medium could significantly reduce the cell viability of SH-SY5Y cells and the expression of neuroplasticity markers MAP2 and Syn; this effect was reversed when the PTAFR gene was silenced (F.


This suggests that PTAFR may serve as a potential AD biomarker and upregulate inflammatory factors through IL10-STAT3 signaling, exacerbating the neuronal inflammatory microenvironment mediated by microgl.

 Figure 5 PTAFR up-regulates inflammatory factors through IL10-STAT3 signaling and worsens the neuronal inflammatory microenvironment mediated by microglia (Source: Junxiu Liu, et .

, Front Aging Neurosci, 2022) The possibility of new therapeutic targets was explored, and the commonly used AD therapeutic drugs in clinical and scientific research such as donepezil, memantine, EGCG, curcumin and huperzine A were selected for targeted molecular docking with PTAFR, and it was found that PTAFR and donepezil were , EGCG and curcumin and other compounds with multiple benzene rings have stronger binding force, and slightly weaker binding force to compounds with stereo conformation such as memantine and huperzin.

These results indicate that PTAFR may interact with some anti-AD drugs with polyphenyl ring structure, and may become a potential target for the development of new strategies for AD treatment and new anti-AD drugs in the futu.

 Figure 6 Research on PTAFR aggravating the neuroinflammatory microenvironment (Source: Junxiu Liu, et .

, Front Aging Neurosci, 2022) Conclusions and discussions, inspiration and prospects A PTAFR highly expressed in brain tissue, blood and cerebrospinal fluid was found, which can be used as a potential novel biomarker for early diagnosis of AD (Figure The mechanism may be related to the up-regulation of inflammatory factors through IL10-STAT3 signaling, which worsens the neuronal inflammatory microenvironment mediated by microglia and exacerbates neuronal damage (F.


In addition, PTAFR may also interact to some extent with anti-AD drugs (Figure
The findings of this study provide a new biomarker PTAFR for the early diagnosis of AD, and provide new ideas for the discovery of new targets for AD therapeutic intervention and the design strategy for the development of new anti-AD dru.

This study also has certain limitations, such as whether silencing PTAFR can further interfere with the immune microenvironment around neurons by affecting the IL10-STAT3 pathway in the brain of APP/PS1 mice, which still needs to be verifi.

In addition, although the authors used MOE software to molecularly dock PTAFR with various potential anti-AD drugs, whether the docked drugs can improve the inflammatory microenvironment in the brain of AD patients by binding to PTAFR as expected, still needs further study Research in dep.

Link to the original text: https:// .

Junxiu Liu is the first author of the paper, and Professor Mingyan Liu is the first corresponding author of the pap.

Liu Junxiu (first from the left), Liu Mingyan (middle) (Photo provided by: Department of Pharmacology, School of Pharmacy, China Medical University) About the corresponding authors: ‍‍‍‍‍Liu Mingyan, professor, master tutor, researching on the pathogenesis of neurodegenerative diseases and new drug developme.

As the corresponding author or the first author, he has published articles in internationally renowned journals such as Eur J Med Chem, Mol Neurobiol, Exp Mol Med, Mol Nutr Food R.
Presided over the National Natural Science Foundation of China and the key projects of the Liaoning Provincial Department of Science and Technology and the Department of Education, and participated in a number of new drug creation projects of the Ministry of Science and Technology and provincial and municipal projec.
, Talent recruitment [1] "Logical Neuroscience" is looking for an associate editor/editor/operation position (online office) Selected articles from previous issues [1] PNAS︱Feng Guoping's laboratory reveals the important role of the front-end thalamic loop in working memory 【2】Mol Psychiatry︱Keqiang Ye’s group reveals that inflammation-activated C/EBPβ/AEP signaling pathway mediates high-fat diet-induced diabetes and Alzheimer’s disease 【3】PNAS︱Changhe Wang’s group reveals synaptic exocytosis- New mechanism of endocytosis balance 【4】Autophagy︱Ye Yihong’s research group reveals new molecular mechanism of neuronal ceroid lipofuscin deposition: DNAJC5/CSPα gene mutation leads to lysosomal homeostasis imbalance 【5】J Neuroinflammation | Wang Yilong team reports blood inflammation New evidence for the relationship between markers and cerebral small vessel disease【6】Science︱Neural mechanism of non-cued goal-directed behavior【7】Front Psychiatry︱Yang Zhi group reported a state anxiety tracking model with high temporal resolution【8】Neural Regen Res Review︱The advantages of Rho kinase and its inhibitor Fasduil in the treatment of neurodegenerative diseases【9】Nat Neurosci︱He Yanlin/Xu Yong team cooperated to report a new mechanism of anorexia nervosa【10】Transl Psychiatry︱Wang Xueyi team in early childhood stress New Progress in Brain Mechanism Research on Cognitive Function in Adulthood Recommended for high-quality scientific research training courses [1] Symposium on Single-Cell Sequencing and Spatial Transcriptomics Data Analysis (Tencent Online Conference on June 11-12) [2] Diaphragm Symposium on Clamp and Optogenetics and Calcium Imaging Technology May 21-22 Tencent Conference References (swipe up and down to read) [1]2020 Alzheimer's disease facts and figur.

Alzheimers Dement, 202[2]Robinson M, Lee BY, Hane .

Recent Progress in Alzheimer's Disease Research, Part 2: Genetics and Epidemiolo.

J Alzheimers Dis, 2017, 57(2): 317-33[3]McKhann GM, Knopman DS,Chertkow H, et .

The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disea.

Alzheimers Dement, 2011, 7(3): 263-26[4] Kerbler GM, Fripp J, Rowe CC, et .

Basal forebrain atrophy correlates with amyloid beta burden in Alzheimer's disea.

Neuroimage Clin, 2015, 7: 105-11 [5]Hyman BT, Phelps CH, Beach TG, et .

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disea.

Alzheimers Dement, 2012, 8(1): 1-1[6]Sperling RA, Aisen PS, Beckett LA, et .

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disea.

Alzheimers Dement, 2011, 7(3): 280-29[7]Hane FT, Robinson M, Lee BY, et .

Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatme.

J Alzheimers Dis, 2017, 57(3): 645-66[8]Ma G, Liu M, Du K, et .

Differential Expression of mRNAs in the Brain Tissues of Patients with Alzheimer's Disease Based on GEO Expression Profile and Its Clinical Significan.

Biomed Res Int, 2019, 2019: 817914 [9] Hou T, Lou Y, Li S, et .

Kadsurenone is a useful and promising treatment strategy for breast cancer bone metastases by blocking the PAF/PTAFR signaling pathw.

Oncol Lett, 2018, 16(2): 2255-226[10]Zhao XS, Ren Y, Wu Y, et .

MiR-30b-5p and miR-22-3p restrain the fibrogenesis of post-myocardial infarction in mice via targeting PTA.

Eur Rev Med Pharmacol Sci, 2020, 24(7): 3993-400[11]Latchoumycandane C, Nagy LE, McIntyre .

Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumpti.

Free Radic Biol Med , 2015, 86: 179-19[12]Latchoumycandane C, Hanouneh M, Nagy LE, et .

Inflammatory PAF Receptor Signaling Initiates Hedgehog Signaling and Kidney Fibrogenesis During Ethanol Consumpti.

PLoS One, 2015, 10(12): e014569 [13]Bhosle VK, Rivera JC, Zhou TE, et .

Nuclear localization of platelet-activating factor receptor controls retinal neovascularizati.

Cell Discov, 2016, 2: 1601 End of this paperFree Radic Biol Med, 2015, 86: 179-19[12]Latchoumycandane C, Hanouneh M, Nagy LE, et .

Inflammatory PAF Receptor Signaling Initiates Hedgehog Signaling and Kidney Fibrogenesis During Ethanol Consumpti.

PLoS One, 2015, 10(12 ): e014569[13]Bhosle VK, Rivera JC, Zhou TE, et .

Nuclear localization of platelet-activating factor receptor controls retinal neovascularizati.

Cell Discov, 2016, 2: 1601 End of paperFree Radic Biol Med, 2015, 86: 179-19[12]Latchoumycandane C, Hanouneh M, Nagy LE, et .

Inflammatory PAF Receptor Signaling Initiates Hedgehog Signaling and Kidney Fibrogenesis During Ethanol Consumpti.

PLoS One, 2015, 10(12 ): e014569[13]Bhosle VK, Rivera JC, Zhou TE, et .

Nuclear localization of platelet-activating factor receptor controls retinal neovascularizati.

Cell Discov, 2016, 2: 1601 End of paper