Correlations of brain network functional connectivity alterations with cerebrospinal fluid pathological markers in patients with Alzheimer's disease / 中华神经医学杂志

Objective:To explore the correlations of brain network functional connectivity (FC) alterations with cerebrospinal fluid (CSF) pathological biomarkers in patients with Alzheimer's disease (AD).Methods:A total of 39 patients with cognitive impairment, admitted to Department of Neurology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University from January 2020 to December 2022 were recruited; 23 patients were with AD and 16 with non-AD. Clinical data were compared between the 2 groups. Resting-state functional MRI (rs-fMRI) data were collected, and FC differences between brain networks and FC differences within brain networks were compared by independent component analysis. Correlations of FC differences between brain networks and FC differences within brain networks with concentrations of β-amyloid protein 1-42 (Aβ 1-42) and Tau protein in CSF were analyzed. Results:Compared with the non-AD group, AD group had significantly lower Aβ 1-42 in CSF ( P<0.05). Compared with those in the non-AD group, FC alterations between the left frontoparietal network (lFPN) and anterior default mode network (aDMN) and between the visual network (VN) and posterior cingulate cortex (PCC), as well as FC alterations in lFPN, were significantly increased in AD group ( P<0.05). Compared with those in the non-AD group, FC alterations between lFPN and cerebellar network (CEN), and FC alterations in aDMN, sensorimotor network (SMN) and VN were significantly decreased in AD group ( P<0.05). In AD group, FC in SMN was positively correlated with total Tau and phosphorylated-Tau181 in CSF ( P<0.05); FC between VN and PCC was positively correlated with total Tau in CSF ( P<0.05). CSF Aβ 1-42 was positively correlated with FC alterations in aDMN and VN, but negatively correlated with FC in FPN ( P<0.05). Conclusion:In AD patients, characteristic changes in FC within and between multiple brain networks are noted, which are related to changes of Tau protein and Aβ 1-42 in CSF.

Research progress on the relationship between cognitive function and oxidative stress indicators in elderly patients with Alzheimer's disease / 公共卫生与预防医学

Alzheimer' s disease (AD) is a neurodegenerative disease that progresses with age and is clinically characterized by cognitive impairment, memory decline, mental symptoms and behavioral disorders. Oxidative stress emerges when an imbalance exists between the generation of free radicals and the antioxidant capacity to scavenge them in the body, and the resulting oxidative injury is closely related to the occurrence of AD. Oxidative stress leads to the mass production of free radicals, which increases the oxidation of macromolecules of nerve cells, the aggregation of β amyloid (Aβ) and the excessive phosphorylation of tau protein and forms the neurofibrillary tangles, thereby inducing apoptosis of nerve tissue cells. In addition, a large number of free radicals can also cause brain inflammatory response and aggravate nerve tissue injury. This paper mainly reviews the pathogenesis of AD and its relationship with oxidative stress, aiming to provide ideas for clinical research.

Prevention and Treatment of Alzheimer's Disease by Traditional Chinese Medicine via Regulating ROS： A Review / 中国实验方剂学杂志

The pathological mechanism of Alzheimer's disease （AD） is complex， and there are many hypotheses. The mainstream theory is the amyloid-beta protein （Aβ） and Tau protein phosphorylation. Oxidative stress （OS） is a bridge between other hypotheses and mechanisms and plays a key role in many hypotheses. Therefore， the treatment of OS in AD （ADOS） is beneficial in alleviating disease progression. Reactive oxygen species （ROS） is a kind of antioxidant and a kind of oxidation products， with Aβ and Tau protein interactions， activating microglia and astrocytes， triggering inflammation and mitochondrial dysfunction， leading to the deterioration of the environment in the brain， and accelerating the development of disease. ROS， as a signal messenger inducing OS， is widely involved in the progression of AD and may be a new target for the progression of AD. Traditional Chinese medicine （TCM） monomers and compounds play an increasingly important role in the prevention and treatment of AD. Recent studies have found that the effective prevention and treatment of AD by TCM is closely related to the regulation of ROS. There are many studies on the mechanism of TCM in the treatment of AD via regulating ROS， but there is a lack of systematic review. By analyzing and summarizing the literature in China and abroad in recent years， this paper reviewed the generation and physiology of ROS， the mechanism of action of AD， and the prevention of AD by TCM via regulating ROS through relevant ways， so as to provide references for the research on the regulation of ROS by TCM and provide new targets and new methods for the prevention and treatment of AD.

Effects of Lactobacillus Rhamnosus GG on Activated Microglia and Tau Phosphorylation in the Hippocampus of Aged Mice Induced by Anesthesia and Surgery / 中山大学学报(医学科学版)

ObjectiveTo investigate the effects of Lactobacillus rhamnosus GG （LGG）on microglia and Tau phosphorylation in the hippocampus of aged mice induced by anesthesia and surgery. MethodsA total of thirty 18-month-old C57BL/6J mice were randomly divided into three groups： control group， anesthesia surgery group， and anesthesia surgery + LGG group （10 mice/group）. The aged mice were oral administered by NS or LGG 109 CFU 150 μL once a day for 20 days. Then anesthesia surgery group and anesthesia surgery +LGG group received anesthesia with isoflurane and exploratory laparotomy. The activation status of microglia in the hippocampus was detected by immunofluorescence staining 12 hours after surgery. IL-6 concentration changes was detected by ELISA. The expression changes of Tau protein phosphorylation site （Tau-pS202/pT205） and total Tau protein was detected by western blot. ResultsThe microglia in the hippocampus of the control group were in a resting state， and the concentration of inflammatory factor IL-6 was （82.08 ± 12.07） pg/mL in control group. Compared to the control group， the anesthesia surgery group showed microglial cell Microglia were activated， the concentration of inflammatory factors IL-6 increased significantly to （123.7±5.72） pg/mL （P=0.000）， and the expression of phosphorylated Tau-pS202/pT205 increased the hippocampus （P=0.002）. Compared to the anesthesia surgery group， the activated microglia were inhibited， the concentration of IL-6 decreased to （96.68±9.59） pg/mL （P=0.008）， and the expression of phosphorylated Tau-pS202/pT205 reduced significantly in the AS+LGG group （P=0.002）. While there were no significant changes in total Tau protein among 3 groups. ConclusionPreoperative administration of probiotic LGG can alleviate the activation of microglia， increased secretion of inflammatory factors， and increased Tau protein phosphorylation levels in the hippocampus of elderly mice caused by anesthesia surgery.

Mechanism of axonal transport dysfuction of mitochondria in Alzheimer's disease / 中华神经医学杂志

Alzheimer's disease (AD) is a central neurodegenerative disease with still unclear pathogenesis. Recent studies have shown that axonal transport dysfuction of mitochondria may contribute to AD progression. Normal mitochondrial axonal transport mainly involves microtubules, molecular motors and connexins, while AD early pathological changes can damage mitochondrial axonal transport by interfering with these proteins: accumulated β-amyloid (Aβ) impairs the function of molecular motors; abnormally modified Tau protein reduces microtubule stability; mutant presenilin-1 (PS1) can induce phosphorylation of some related proteins by activating glycogen synthase kinase-3β (GSK-3β); all these processes can damage mitochondrial axonal transport, leading to synaptic dysfunction. This review aims to clarify the possible mechanisms of axonal transport dysfuction of mitochondria in AD and provides new ideas for AD treatment.

Recent advance in clinical drug therapy for Alzheimer's disease / 中华神经医学杂志

Alzheimer's disease (AD) is the first degenerative disease of the nervous system, but no drugs have been found to reverse AD progression. Starting from 2 major pathogenesis of AD, namely amyloid beta (Aβ) cascade and Tau protein, this study systematically reviews anti-Aβ or Tau protein AD new drugs that have entered clinical research; this study also expounds their clinical trial findings and mechanisms, and analyzes the reasons for their success or failure to provide a theoretical basis for AD drug exploitation.

Correlations of hippocampal subfield volumes with cerebrospinal fluid biomarkers in patients with Alzheimer's disease / 中华神经医学杂志

Objective:To study the correlations of hippocampal subfield volumes with cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) patients.Methods:Forty-nine patients with cognitive impairment, including 30 AD patients and 19 non-AD patients, were recruited in Department of Neurology, Drum Tower Clinical College, Nanjing University of Chinese Medicine from May 2017 to December 2021. Concentrations of Aβ 1-42, total tau protein and phosphorylated tau protein in CSF were analyzed by enzyme-linked immunosorbent assay (ELISA). Volumes of 12 hippocampal subfields were calculated using FreeSurfer image analysis. Differences of clinical data, neuropsychological scores and CSF biomarker concentrations between the 2 groups were compared. Partial correlation was performed to analyze the correlations of volumes of hippocampal subfields with CSF biomarker concentrations. Results:AD patients had significantly lower Mini-mental State Examination (MMSE) scores and Aβ 1-42 concentration in CSF than non-AD patients ( P<0.05); AD patients had significantly lower volumes of the right hippocampal parasitulum, dentate gyrus and CA4 than non-AD group ( P<0.05); the right parasubiculum volume was negatively correlated with CSF Aβ 1-42 ( r=-0.445, P=0.023) and positively correlated with CSF P-tau ( r=0.393, P=0.047) in AD patients. Volumes of left hippocampus tail, parasubiculum, CA1, molecular layer, dentate gyrus, CA3 and CA4 were negatively correlated with CSF total tau ( P<0.05). No significant correlation was noted between hippocampal subfield volumes and CSF biomarker concentrations in non-AD patients. Conclusion:Some right hippocampal subfields in AD patients atrophy compared with those in non-AD patients with cognitive impairment; the right parasubiculum may play a compensatory role in disease process, while volumes of the left hippocampus decreased with increased CSF total tau.

Effects of Dianxianqing granules on tau protein in P301S mice by regulating mitophagy / 中国药房

OBJECTIVE To study the effects of Dianxianqing granules on the tau protein in P301S mice by regulating mitophagy. METHODS Totally 36 P301S mice were randomly divided into model group， Dianxianqing granule group （12.48 g/kg）， donepezil hydrochloride group （positive control， 1.3 mg/kg）， with 12 mice in each group； another 10 C57BL6 mice were selected as control group. Administration groups were given relevant drug solutions intragastrically， and control group and model group were given constant volume of water intragastrically. The gavage volume was 20 mL/kg， once a day， for consecutive 5 months. During the experiment， the general condition of mice was observed in each group. After the last medication， the learning and memory ability was determined by Y maze test and Morris water maze test； HE staining was used to observe the morphological changes in brain tissue， and Nissl staining was used to observe the structure of neural cells and the number of Nissl bodies in cerebral tissue. Immunohistochemistry was used to detect the expressions of phospho-tau serine 202/threonine 205 （abbreviated as AT8） in brain tissue. Western blot assay was used to determine the expressions of mitophagy-associated proteins [PTEN-induced putative kinase-1 （PINK1）， Parkin， microtubule-associated protein 1 light chain 3B （LC3B）， p62]， synaptic-associated proteins [postsynaptic density protein-95 （PSD-95）， synaptophysin （SYP）， and growth-associated protein-43 （GAP-43）] and the phosphorylation of tau protein [expressed by the phosphorylation levels of serine 199 （Ser199） and Ser202] in brain tissue. RESULTS The mice in E-mail：lnzyxyqy2003@163.com model group showed symptoms such as white hair， decreased body mass， and lower limb paralysis， with incomplete hippocampal structures in their brain tissue， as well as incomplete cell membrane edges and cell structures； the spontaneous alternating response rate， the times of crossing platform， the number of Nissl bodies， the protein expressions of PINK1， Parkin， LC3B， SYP， GAP-43， and PSD-95 were decreased significantly， compared with control group； swimming latency （fourth and fifth day）， the protein expressions of AT8 and p62，the phosphorylation levels of Ser199 and Ser202 were increased or lengthened significantly， compared with control group （P＜0.05 or P＜0.01）. Compared with model group， the above symptoms and indexes of mice were improved significantly in administration groups （P＜0.05 or P＜0.01）. CONCLUSIONS Dianxianqing granules can effectively improve cognitive impairment in P301S mice，the mechanism of which may be associated with inducing mitochondrial autophagy， reducing the hyperphosphorylation of tau protein， up-regulating the expression of synaptic-associated proteins in brain tissue，and repairing damaged neural cells.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats / 中国针灸

OBJECTIVE@#To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD.@*METHODS@#A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected.@*RESULTS@#There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05).@*CONCLUSION@#Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Therapeutic Mechanism of Kai Xin San on Alzheimer's Disease Based on Network Pharmacology and Experimental Validation / 中国结合医学杂志

OBJECTIVE@#To explore the specific pharmacological molecular mechanisms of Kai Xin San (KXS) on treating Alzheimer's disease (AD) based on network pharmacology and experimental validation.@*METHODS@#The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine (ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway.@*RESULTS@#In total, 38 active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta (A β)-glycogen synthase kinase-3 beta (GSK3 β)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo, KXS treatment significantly improved cognitive deficits in AD rats induced by Aβ1-42, decreased the levels of Aβ, p-GSK3β, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1 alpha (PP1A) and PP2A (P<0.05 or P<0.01).@*CONCLUSION@#KXS exerted neuroprotective effects by regulating the Aβ -GSK3β-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.

Theoretical Exploration of Luobing Theory Guides Study on Alzheimer's Disease Based on Neurovascular Protection / 中国实验方剂学杂志

Based on the correlation between Qi and blood in traditional Chinese medicine， the collateral disease theory puts forward that the Qi-collateral go hand in hand with the vessel-collateral of the brain， and to be as close as lips to teeth in structure and function， which is an important basis for the function of brain governing mind. And this theory proposes that deficiency/stagnancy of collateral-Qi， stagnation of collaterals and loss of consciousness are the main pathogenesis of Alzheimer's disease（AD）， which is different from the research strategy of modern medicine focusing on neurons. It is suggested that it is necessary to treat AD from two aspects， including neuronal protection（elimination of pathological products such as β-amyloid and phosphorylated tau protein） and cerebral microvascular protection（protection of cerebral microvascular structure and function， promotion of therapeutic angiogenesis and increase of cerebral blood flow. Tongxinluo capsules is a representative drug for dredging collaterals developed under the guidance of the therapeutic principle of collaterals need circulation， it can protect microvessels and play a neuroprotective role mediated by vascular protection. Clinical studies have confirmed that Tongxinluo capsules can effectively treat AD， vascular dementia and cognitive impairment related diseases， which can provide new ideas and effective treatment ways to prevent and treat AD from neurovascular protection in a comprehensive manner.

Amelioration of Cognitive Dysfunction in Diabetic Rats by Jianpi Qinghua Prescription / 中国实验方剂学杂志

ObjectiveTo explore the amelioration of cognitive dysfunction in diabetes mellitus （DM） by Jianpi Qinghua prescription （JPQH） based on type 2 diabetes （T2DM） model rats. MethodFifty healthy male Wistar rats of SPF grade were randomly divided into control group （n=10） and experimental group （n=40）. The rats in the control group were fed conventionally， while those in the experimental group were fed on a high-sugar， high-fat diet for six weeks and administered with streptozotocin （STZ） for the induction of the DM model. The model rats were randomly divided into model group， sitagliptin group （1.2 g·L-1）， pioglitazone group （0.8 g·L-1）， and JPQH group （1.3 g·mL-1）， with 10 rats in each group. After six weeks of drug intervention， the changes in body weight， blood glucose， and other related indexes of each group were recorded. Enzyme-linked immunosorbent assay （ELISA） was performed to detect the levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6） in the peripheral blood and brain. The Morris water maze test was used to evaluate the cognitive function in rats. Hematoxylin-eosin （HE） staining was used to observe the pathological morphology of the hippocampal CA region. The amyloid β-protein 40 （Aβ40） level was detected by immunohistochemistry. The protein expression of t-tau and p-tau in hippocampal neurons of rats was detected by Western blot. ResultCompared with blank group， the body weight of model group was significantly decreased （P<0.05）， blood glucose level was significantly increased （P<0.01）， inflammatory cytokines TNF-α and IL-1β were increased （P<0.05）， learning and spatial ability were significantly decreased （P<0.01）， the arrangement of hippocampal cells was loose and disordered， and the intercellular space was significantly increased. The number of cells decreased significantly， and the expression of Aβ40 increased significantly. and increased t-tau and p-tau protein content in the hippocampus （P<0.01）. Compared with model group， the JPQH group showed reduced blood glucose （P<0.01）， decreased TNF-α and IL-1β levels in the peripheral blood and cerebrospinal fluid （P<0.05）， a downward trend of IL-6 without a statistical difference， improved learning and spatial memory ability （P<0.01）， densely arranged cells in the hippocampal CA1 area， increased cell number， reduced Aβ40 expression， and decreased p-tau protein expression （P<0.05）. ConclusionJPQH can prevent cognitive dysfunction in DM by reducing inflammatory factor levels， decreasing neurotoxicity caused by Aβ40 deposition， and inhibiting hyperphosphorylation of tau protein in DM rats.

Effect of aluminum exposure on abnormal phosphorylationof tau protein in PC12 cells of rats / 预防医学

Objective @#To investigate the effect of aluminum exposure on expression of miR-497-5p, wingless murine breast cancer virus integration site family member 3a (Wnt3a), β-catenin protein, glycogen synthase kinase-3β (GSK-3β) protein and tau protein in rat adrenal pheochromocytoma PC12 cells, so as to provide insight into unraveling the mechanisms underlying aluminum exposure-induced abnormal phosphorylation of tau protein.@* Methods@# PC12 cells were exposed to Al(mal)3 at concentrations of 0, 100, 200, 400 μmol/L for 24 h. The viability of PC12 cells was measured using cell counting kit-8 (CCK-8) assay. The relative expression of miR-497-5p and Wnt3a was detected using a real-time fluorescent quantitative PCR (RT-qPCR) assay, and the expression of Wnt3a, β-catenin, GSK-3β, P-GSK-3β (Ser9), tau and p-tau (Ser396) proteins were determined using Western blotting. @*Results @#The viability of PC12 cells appeared a tendency towards a decline with the increase of aluminum dose (Ftrend=323.473, P=0.001). RT-qPCR assay detected that the relative miR-497-5p expression appeared a tendency towards a rise with the increase of aluminum dose (Ftrend=14.888, P=0.031), and the relative Wnt3a expression appeared a tendency towards a decline with the increase of aluminum dose (Ftrend=165.934, P<0.001). The miR-497-5p expression negatively correlated with the relative Wnt3a expression (r=-0.693, P=0.012). The expression of Wnt3a (Ftrend=357.656, P=0.001), β-catenin (Ftrend=208.750, P=0.001) and p-GSK-3β (Ser9) proteins (Ftrend=512.583, P<0.001) appeared a tendency towards a decline with the increase of aluminum dose, and the expression of GSK-3β (Ftrend=39.965, P<0.001), tau (Ftrend=277.929, P=0.006) and p-tau (Ser396) proteins (Ftrend=96.247, P=0.002) appeared a tendency towards a rise with the increase of aluminum dose. @*Conclusion@# Up-regulation of miR-497-5p and GSK-3β expression and down-regulation of Wnt3a and β-catenin expression may be a mechanism underlying aluminum exposure-induced abnormal phosphorylation of tau protein.

Effect of Danzhi Xiaoyaosan on Phosphorylation of Tau Protein in Rats with Alzheimer's Disease Based on PP2A and GSK-3β / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Danzhi Xiaoyaosan on the phosphorylation of tau protein and different sites of glycogen synthase kinase-3β （GSK-3β） and phosphoseryl/suanyl phosphate protein phosphatase 2A （PP2A） in the hippocampus of rats with Alzheimer's disease （AD） and its mechanism. MethodThe rat model of AD was established by injecting okadaic acid into the bilateral hippocampus of 90 male Wistar rats in SPF grades. The rats with successful modeling were selected and randomly divided into model group， aricept group （0.5 mg·kg-1）， and Danzhi Xiaoyaosan high， medium， and low groups （17.55， 8.77， and 4.38 g·kg-1）， and then gavaged for 42 d， once a day. Morris water maze was used to detect the learning and memory ability of rats， Nissl's staining was used to observe the morphological structure of neurons in the hippocampus， and Real-time polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression levels of tau protein， GSK-3β， and PP2A. Western blot was used to determine the protein expression levels of tau protein， GSK-3β， and PP2A. ResultAs compared with the control group， the learning and memory abilities of the rats in the model group were significantly decreased （P<0.01）， and the hippocampal CA3 region cells had abnormal structure， disorderly arrangement， and decreased number. The expression levels of GSK-3β mRNA， GSK-3β， p-GSK-3β-Tyr216， p-PP2A， and p-tau were increased in the model group as compared with the control group （P<0.01）， and those of p-GSK-3β-Ser9 and PP2A decreased significantly （P<0.01）. As compared with the model group， the learning and memory ability of the Aricept group and the Danzhi Xiaoyaosan groups were improved （P<0.05， P<0.01）， and the cell morphology and the number of hippocampal CA3 regions were better. The mRNA expression levels of PP2A and tau in the Aricept group were significantly up-regulated （P<0.05）， the mRNA expression level of GSK-3β was significantly down-regulated （P<0.01）， and the protein expression levels of GSK-3β， p-GSK-3β-Tyr216， and p-PP2A were down-regulated （P<0.05， P<0.01）， and the protein expression level of PP2A was significantly up-regulated （P<0.01）. As compared with the model group， the mRNA expression level of PP2A in the high-dose Danzhi Xiaoyaosan group was significantly up-regulated （P<0.01）， and that of GSK-3β was significantly down-regulated （P<0.01）， whereas the protein expression levels of p-PP2A， p-GSK-3β-Tyr216， and p-tau were down-regulated （P<0.05， P<0.01）， and the protein expression level of PP2A was significantly up-regulated （P<0.01）. As compared with the model group， the mRNA expression level of GSK-3β was significantly down-regulated in the medium-dose Danzhi Xiaoyaosan group （P<0.01）， the protein expression levels of GSK-3β， p-GSK-3β-Tyr216， and p-tau were down-regulated （P<0.05， P<0.01）， and the protein expression level of PP2A was significantly up-regulated （P<0.01）. As compared with the model group， the mRNA expression level of PP2A was significantly up-regulated in the low-dose Danzhi Xiaoyaosan group （P<0.01）， and that of GSK-3β was significantly down-regulated （P<0.01）， whereas the protein expression levels of GSK-3β and p-GSK-3β-Tyr216 were down-regulated （P<0.05， P<0.01）， and those of p-GSK-3β-Ser9 and PP2A were significantly up-regulated （P<0.01）. ConclusionDanzhi Xiaoyaosan can improve the learning and memory ability of rats with AD， and its mechanism may be related to the regulation of the activities of GSK-3β and PP2A protein-related sites and the phosphorylation of tau protein.

Association of cerebral microbleeds with cognitive impairment and hyperphosphorylated Tau protein level in patients with cerebral infarction and obstructive sleep apnea-hypopnea syndrome / 中风与神经疾病杂志

@#Objective To observe cerebral microbleeds （CMBs）, cognitive function, and the protein expression level of hyperphosphorylated Tau （P-Tau） in patients with cerebral infarction and obstructive sleep apnea-hypopnea syndrome （OSAHS）, to analyze their differences between the cerebral infarction+OSAHS group and the control group, and to further investigate the degree of cognitive impairment in patients with cerebral infarction and OSAHS and the association between the protein expression level of P-Tau and CMBs. Methods A prospective analysis was performed for 199 patients with cerebral infarction who were admitted to Stroke Center in our hospital from December 2019 to December 2022, among whom there were 94 patients with OSAHS （cerebral infarction+OSAHS group） and 105 patients without OSAHS （control group）, and CMBs and Montreal Cognitive Assessment （MoCA） score were assessed for the two groups. The two groups were compared in terms of changes in the protein expression level of P-Tau before treatment and after 7 and 14 days of treatment. The receiver operating characteristic （ROC） curve was used to describe the predictive efficacy of P-Tau protein level before treatment for the cognitive function of patients with cerebral infarction CMBs and OSAHS, and the Pearson correlation coefficient was used to investigate the correlation of the scores of each dimension of MoCA scale with P-Tau protein level before treatment. With the score of MoCA scale as the basis for assessing the degree of cognitive impairment, 94 patients were divided into mild impairment group, moderate impairment group, and severe impairment group, and P-Tau protein level before treatment was compared between the three groups. Results Compared with the patients in the control group, the patients with cerebral infarction and OSAHS had a significantly lower MoCA score （P<0.05） and a higher occurrence rate of CMBs, especially in those with mild grade. Before treatment, the cerebral infarction+OSAHS group had a significantly higher P-Tau protein level than the control group （P<0.05）, and after 7 and 14 days of treatment, the cerebral infarction+OSAHS group had no significant change in P-Tau protein level （P>0.05）, while the control group had a significant reduction in P-Tau protein level （P<0.05）. P-Tau protein level before treatment showed a sensitivity of 67.31% and a specificity of 90.48% in the diagnosis of cognitive impairment in the patients with cerebral infarction CMBs and OSAHS, and the Pearson correlation analysis showed that the scores of visuospatial/executive, attention and computational ability, language, abstraction, and delayed memory in MoCA scale were negatively correlated with P-Tau protein level before treatment in these patients （P<0.05）. There was a significant difference in P-Tau protein level before treatment between the mild impairment group, the moderate impairment group, and the severe impairment group （P<0.05）. Conclusion P-Tau protein level before treatment is associated with cognitive impairment in patients with cerebral infarction CMBs and OSAHS, which can guide the diagnosis and severity assessment of the disease in clinical practice.

Expression of serum macrophage migration inhibitory factor and Tau protein in patients with severe hypertensive intracerebral hemorrhage and their relationships with clinical outcome / 中风与神经疾病杂志

@#Objective To explore the expression levels of serum macrophage migration inhibitory factor(MIF) and Tau protein in patients with severe hypertensive intracerebral hemorrhage(HICH),and analyze the relationships between their levels and patient outcome,and to provide a reference for clinical treatment of such patients. Methods We included 120 patients with severe HICH and 50 age-and sex-matched healthy controls from health examination in Ziyang Hospital of West China Hospital of Sichuan University from January 2019 to November 2022.The MIF and Tau protein levels of the two groups were compared. After a follow-up of more than half a year,the patients were divided into poor-prognosis group and good-prognosis group according to the defined criteria to compare their levels of MIF and Tau protein. The receiver operating characteristic(ROC) curve and Kaplan-Meier method were used to explore the critical values of MIF and Tau protein levels for patients with poor prognosis and the relationships with the clinical outcome of severe HICH. Results The levels of serum MIF and Tau protein in the patients with severe HICH were significantly higher than those in the control group(P<0.05). The poor-prognosis group showed significantly higher levels of serum MIF and Tau protein than the good-prognosis group(P<0.05). The ROC curve showed that the cutoff points of serum MIF and Tau protein levels for predicting poor prognosis were 64.43 ng/L and 216.25 pg/ml,respectively. The area under the curve for using MIF to predict poor prognosis was 0.815(95%CI=0.759-0.849),with sensitivity of 81.56% and specificity of 83.24%,and those values for using Tau protein to predict poor prognosis were 0.847(95%CI=0.764-0.831),82.26%,and 79.68%,respectively,all at high levels. Patients with serum MIF level <64.43 ng/L had significantly better survival than those with serum MIF level ≥ 64.43 ng/L(P<0.05 by log-rank test). Patients with serum Tau protein level<216.25 pg/ml had significantly better survival than those with serum Tau protein level ≥216.25 pg/ml(P<0.05 by log-rank test). Conclusion Patients with severe HICH had significantly higher serum MIF and Tau protein levels than healthy people. The patients with poor prognosis had significantly higher serum MIF and Tau protein levels than those with good prognosis. Serum MIF and Tau protein levels were closely related to the clinical outcome of the patients,which can be used as effective indicators to predict the prognosis of patients with HICH.

Research progress on the use of Rhizoma coptidis extract against Alzheimer's disease / 中华老年医学杂志

Rhizoma coptidis extract has a variety of pharmacological activities, including alleviating cognitive impairment in Alzheimer's disease(AD). The main mechanisms of its anti-AD activity include reducing the production of amyloid β(Aβ), inhibiting the phosphorylation of Tau protein, inhibiting cholinesterase, anti-inflammation, anti-oxidation, improving apoptosis, etc.This paper reviewed the anti-AD effect of Rhizoma coptidis extract and the specific mechanisms, aiming to provide a theoretical basis for relevant research and clinical practice.

The Discovery of Putative Small Molecules via Ligand-based Pharmacophore Modelling Targeting Human Tau Protein for an Effective Treatment of Parkinson’s Disease

@#Introduction: The human tau protein is a key protein involved in various neurodegenerative disease (NDs) including Parkinson’s disease (PD). The protein has high tendency to aggregate into oligomers, subsequently generating insoluble mass in the brain. Symptoms of PD include tremor, bradykinesia, rigidity, and postural instability. Currently drugs for PD treatment are only symptom-targeted while effective therapeutic treatment remains a challenge. The objective of this study is to identify novel promising anti-PD drugs using computational techniques. Method: ligand-based (LB) receptor modelling was conducted using LigandScout, validated and subjected to Glide XP docking, virtual screening, ADMET, and molecular dynamics predictions. Results: The adopted LB modelling generated pharmacophoric features of 5 hydrogen bond donors, 1 aromatic rings, and 7 hydrogen bond acceptors. The validation result indicated GH score of 0.73 and EF of 36.30 as validation protocols, probing it to be an ideal model. Using 3D query of the modelling a total of 192 compounds were retrieved from interbioscreen database containing 70,436 natural compounds. Interestingly, ligands 1, 2, 3, 4 and 5 orderly indicated higher binding affinities to the receptor with Glide XP docking of -7.451, -7.368, -7.101, -6.878, and -6.789 compared to a clinical drug Anle138b with -4.552 kcal/mol respectively. Furthermore, molecular dynamics and pkCSM pharmacokinetics demonstrated ligands 1, 2, & 4 having better stability and low toxicity profiles compared to the reference. Conclusion: In summary, the study pave way for discovery of small molecules that could be recommended as adjuvant /single candidate as ant-PD candidates upon further translational study.

Neuroprotective and mechanistic study of GJ-4 on okadaic acid-induced memory impairment in mice / 药学学报

GJ-4 is crocin enrichments extracted from Gardenia jasminoides J. Ellis, and our previous studies have shown that GJ-4 significantly improved learning and memory impairment induced by Aβ in mice. Herein, a memory deficit model was developed by injecting okadaic acid (OA) into the lateral ventricle of mice, and the neuroprotection and underlying mechanism of GJ-4 on neuronal injury caused by Tau hyperphosphorylation were investigated. The Animal Care & Welfare Committee, Institute of Materia Medica, CAMS & PUMC has approved all procedures (No.00000318). GJ-4 at different doses was intragastric administration to mice for 16 days. Step-down test and Morris water maze test showed that GJ-4 could significantly improve OA-induced memory impairment in mice, and reduced the loss of Nissl bodies in the hippocampus of mice. GJ-4 could also decrease the phosphorylation level of Tau protein at Ser396, Thr231 and Ser404 via increasing protein phosphatase 2A (PP2A) activity and inhibiting glycogen synthase kinase-3β (GSK-3β) activity. Besides, further researches indicated that GJ-4 could inhibit the level of oxidative stress in the brain of OA mice, reduce neuronal apoptosis and inhibit the neuroinflammation mediated by activation of astrocytes in the hippocampus of mice, and eventually achieve its effects in improving learning and memory impairment in mice. According to these findings, we anticipated that GJ-4 might be a potential therapeutic drug for Alzheimer's disease.

Proteína tau como biomarcador en Alzheimer preclínico / Tau protein as a biomarker in preclinical Alzheimer's disease

El desarrollo de biomarcadores de la proteína tau para el diagnóstico temprano de la enfermedad de Alzheimer (EA) emerge como un desafío fundamental, pudiendo mejorar la efectividad de un tratamiento preventivo o que enlentezca la progresión de la enfermedad. Esta revisión analiza las evidencias que justificarían el uso de la proteína tau como biomarcador en Alzheimer preclínico. Para esto se seleccionaron artículos científicos (2011-2021) que incluyeran a la proteína tau en plasma y plaquetas como biomarcador. La presencia de la proteína tau fosforilada en el líquido cefalorraquídeo presenta limitaciones por su carácter invasivo mientras que las técnicas de imagen son costosas. La medición de tau en plaquetas se correlaciona con la severidad de la demencia, y sería útil en el seguimiento de la EA. Sin embargo, la pertinencia de su uso en la detección temprana de EA se mantiene en discusión. La presencia de proteína tau fosforilada en plasma correspondería al biomarcador con mayor nivel de desarrollo, respecto de beta amiloide. La proteína tau plasmática detecta la EA con gran precisión en casos de demencia y ha sido validada por estudios neuropatológicos. p-tau217 plasmática medida por primera vez junto a técnicas de imagen, fue importante en la etapa preclínica de EA pudiendo predecir la formación de ovillos neurofibrilares. La correlación entre especies fosforiladas de tau en plasma y EA preclínica ha sido bien establecida, por lo que su uso como biomarcador podría ser de utilidad para la comprensión del proceso fisiopatológico de la neurodegeneración y la detección temprana de EA

The development of tau protein biomarkers for the early diagnosis of Alzheimer's disease (AD) emerges as a fundamental challenge, which may improve the effectiveness of preventive treatment or slow the progression of the disease. This review analyzes the evidence that would justify the use of tau protein as a biomarker in preclinical Alzheimer's disease. For this purpose, we selected scientific articles (2011-2021) that included tau protein in plasma and platelets as a biomarker. Phosphorylated tau protein in cerebrospinal fluid has limitations due to its invasiveness, while imaging techniques are expensive. The tau measurement in platelets correlates with the severity of dementia and would be helpful in the follow-up of AD. However, the relevance of its use in the early detection of AD remains under discussion. Plasma phosphorylated tau protein would correspond to the biomarker with the highest level of development for beta-amyloid. Plasma tau protein detects AD with high accuracy in cases of dementia, and neuropathological studies validate its use. Plasma p-tau217 measured for the first time with imaging techniques was important in preclinical AD and could predict the formation of neurofibrillary tangles. The correlation between plasma phosphorylated tau species and preclinical AD is well-established, so its use as a biomarker would help understand the pathophysiological process of neurodegeneration and early AD detection.