Tripterygium glycosides liposome(TPGL) were prepared by thin film-dispersion method, which were optimized accor-ding to their morphological structures, average particle size and encapsulation rate. The measured particle size was(137.39±2.28) nm, and the encapsulation rate was 88.33%±1.82%. The mouse model of central nervous system inflammation was established by stereotaxic injection of lipopolysaccharide(LPS). TPGL and tripterygium glycosides(TPG) were administered intranasally for 21 days. The effects of intranasal administration of TPG and TPGL on behavioral cognitive impairment of mice due to LPS-induced central ner-vous system inflammation were estimated by animal behavioral tests, hematoxylin-eosin(HE) staining of hippocampus, real-time quantitative polymerase chain reaction(RT-qPCR) and immunofluorescence. Compared with TPG, TPGL caused less damage to the nasal mucosa, olfactory bulb, liver and kidney of mice administered intranasally. The behavioral performance of treated mice was significantly improved in water maze, Y maze and nesting experiment. Neuronal cell damage was reduced, and the expression levels of inflammation and apoptosis related genes [tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), BCL2-associated X(Bax), etc.] and glial activation markers [ionized calcium binding adaptor molecule 1(IBA1) and glial fibrillary acidic protein(GFAP)] were decreased. These results indicated that liposome technique combined with nasal delivery alleviated the toxic side effects of TPG, and also significantly ameliorated the cognitive impairment of mice induced by central nervous system inflammation.
Mice ; Animals ; Tripterygium ; Liposomes ; Glycosides/therapeutic use* ; Administration, Intranasal ; Lipopolysaccharides ; Central Nervous System ; Cognitive Dysfunction/drug therapy* ; Inflammation/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Cardiac Glycosides

Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.
Female ; Humans ; Male ; Alzheimer Disease/pathology* ; CCAAT-Enhancer-Binding Protein-beta/metabolism* ; Cognitive Dysfunction/metabolism* ; Signal Transduction ; Follicle Stimulating Hormone

This study aims to explore the effect of preventive administration of Yigong Powder on the learning and memory abilities of the mouse model of aging induced by D-galactose and decipher the underlying mechanism, so as to provide a basis for the application of Yigong Powder in the prevention and treatment of cognitive decline. Forty KM mice were randomized into control, model, donepezil(1.5 mg·kg~(-1)), and high-dose(7.5 g·kg~(-1)) and low-dose(3.75 g·kg~(-1)) Yigong Powder groups. The mice in other groups except the control group were injected with D-galactose(200 g·kg~(-1)) at the back of the neck for the modeling of aging. At the same time, the mice were administrated with corresponding drugs by gavage for one month. Morris water maze was used to examine the learning and memory abilities of the mice. Hematoxylin-eosin staining was employed to observe the pathological and morphological changes of the hippocampus. The immunofluorescence assay was employed to detect the expression of ionized calcium-binding adapter molecule 1(IBA1), glial fibrillary acidic protein(GFAP), chemokine C-X-C-motif ligand 12(CXCL12), chemokine C-X-C-motif receptor 4(CXCR4) in the hippocampus and observe the positional relationship between IBA1, GFAP, and CXCR4. Western blot was employed to determine the protein levels of extracellular regulated kinase(ERK), p-ERK, and tumor necrosis factor receptor 1(TNFR1). Enzyme-linked immunosorbent assay was employed to measure the levels of glutamate and tumor necrosis factor(TNF-α) in the brain tissue and the level of TNF-α in the serum and spleen. Yigong Powder significantly shortened the escape latency, increased the times crossing platforms, and prolonged the cumulative time in quadrants of the aging mice. It alleviated the nerve cell disarrangement, increased intercellular space, and cell degeneration or death in the hippocampus and reduced the pathology score of the damaged nerve. Moreover, Yigong Powder reduced the positive area of IBA1 and GFAP, reduced the levels of TNF-α in the brain tissue, serum, and spleen, and decreased spleen index. Furthermore, Yigong Powder decreased the average fluorescence intensity of CXCL12 and CXCR4, reduced CXCR4-positive astrocytes and microglia, down-regulated the protein levels of p-ERK/ERK and TNFR1, and lowered the level of glutamate in the brain tissue. This study showed that the preventive administration of Yigong Powder can ameliorate the learning and memory decline of the D-galactose-induced aging mice by regulating the immune function of the spleen and the CXCL12/CXCR4 signaling in the brain to reduce glutamate release. However, the mechanism of Yigong San in preventing and treating dementia via regulating spleen and stomach function remains to be studied.
Mice ; Animals ; Powders ; Receptors, Tumor Necrosis Factor, Type I ; Glutamic Acid ; Tumor Necrosis Factor-alpha/metabolism* ; Galactose/adverse effects* ; Disease Models, Animal ; Cognitive Dysfunction/prevention & control* ; Chemokines ; Drugs, Chinese Herbal

Tu-Xian decoction (TXD), a traditional Chinese medicine (TCM) formula, has been frequently administered to manage diabetic cognitive impairment (DCI). Despite its widespread use, the mechanisms underlying TXD's protective effects on DCI have yet to be fully elucidated. As a significant regulator in neurodegenerative conditions, death-associated protein kinase-1 (DAPK-1) serves as a focus for understanding the action of TXD. This study was designed to whether TXD mediates its beneficial outcomes by inhibiting DAPK-1. To this end, a diabetic model was established using Sprague-Dawley (SD) rats through a high-fat, high-sugar (HFHS) diet regimen, followed by streptozotocin (STZ) injection. The experimental cohort was stratified into six groups: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD groups. Following a 12-week treatment period, various assessments-including blood glucose levels, body weight measurements, Morris water maze (MWM) testing for cognitive function, brain magnetic resonance imaging (MRI), and histological analyses using hematoxylin-eosin (H&E), and Nissl staining-were conducted. Protein expression in the hippocampus was quantified through Western blotting analysis. The results revealed that TXD significantly improved spatial learning and memory abilities, and preserved hippocampal structure in diabetic rats. Importantly, TXD administration led to a down-regulation of proteins indicative of neurological damage and suppressed DAPK-1 activity within the hippocampal region. These results underscore TXD's potential in mitigating DCIvia DAPK-1 inhibition, positioning it as a viable therapeutic candidate for addressing this condition. Further investigation into TXD's molecular mechanisms may elucidate new pathways for the treatment of DCI.
Animals ; Rats ; Brain/metabolism* ; Cognitive Dysfunction/drug therapy* ; Diabetes Mellitus, Experimental/metabolism* ; Hippocampus ; Rats, Sprague-Dawley

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Cognitive Dysfunction/complications* ; DNA Methylation ; Homocysteine/metabolism* ; Hyperhomocysteinemia/metabolism* ; Rats ; Stress, Psychological/physiopathology*

Amyloid beta (Aβ) plaques are one of the hallmarks of Alzheimer's disease (AD). However, currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans. It has been found that there are different types of Aβ plaque (diffuse and focal types) in the postmortem human brain. In this study, we aimed to investigate the correlations among different types of Aβ plaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China. The results indicated that focal plaques, but not diffuse plaques, significantly increased with age in the human hippocampus. We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes (measured by the "ABC" scoring system) and cognitive decline (measured by the Everyday Cognitive Insider Questionnaire). Furthermore, most of the focal plaques were co-localized with neuritic plaques (identified by Bielschowsky silver staining) and accompanied by microglial and other inflammatory cells. Our findings suggest the potential of using focal-type but not general Aβ plaques as biomarkers for the neuropathological evaluation of AD.
Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor ; Brain/pathology* ; Cognitive Dysfunction/pathology* ; Hippocampus/metabolism* ; Humans ; Neuroinflammatory Diseases ; Plaque, Amyloid/pathology*

OBJECTIVES: To evaluate the effect of echinacoside (ECH) on cognitive dysfunction in post cerebral stroke model rats. METHODS: The post stroke cognitive impairment rat model was created by occlusion of the transient middle cerebral artery (MCAO). The rats were randomly divided into 3 groups by a random number table: the sham group (sham operation), the MCAO group (received operation for focal cerebral ischemia), and the ECH group (received operation for focal cerebral ischemia and ECH 50 mg/kg per day), with 6 rats in each group. The infarct volume and spatial learning were evaluated by triphenyl tetrazolium chloride staining and Morris water maze. The expression of α7nAChR in the hippocampus was detected by immunohistochemistry. The contents of acetylcholine (ACh), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and catalase (CAT) were evaluated by enzyme linked immunosorbent assay. The neural apoptosis and autophagy were determined by TUNEL staining and LC3 staining, respectively. RESULTS: ECH significantly lessened the brain infarct volume and ameliorated neurological deficit in infarct volume and water content (both P<0.01). Compared with MCAO rats, administration of ECH revealed shorter escape latency and long retention time at 7, 14 and 28 days (all P<0.01), increased the α7nAChR protein expression, ACh content, and ChAT activity, and decreased AChE activity in MCAO rats (all P<0.01). ECH significantly decreased MDA content and increased the GSH content, SOD, and CAT activities compared with MCAO rats (all P<0.05). ECH suppressed neuronal apoptosis by reducing TUNEL-positive cells and also enhanced autophagy in MCAO rats (all P<0.01). CONCLUSION ECH treatment helped improve cognitive impairment by attenuating neurological damage and enhancing autophagy in MCAO rats.
Acetylcholinesterase ; Animals ; Autophagy ; Brain Ischemia/metabolism* ; Cerebral Infarction ; Cognitive Dysfunction/drug therapy* ; Glutathione/metabolism* ; Glycosides ; Infarction, Middle Cerebral Artery/drug therapy* ; Neuroprotective Agents/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy* ; Stroke/drug therapy* ; Superoxide Dismutase/metabolism* ; alpha7 Nicotinic Acetylcholine Receptor

The aim of the present study was to explore the correlation between ptk2b/PTK2B (protein tyrosine kinase 2 beta, a ptk2b-encoded protein) and the level of low density lipoprotein receptor-related protein-1 (LRP-1), as well as to uncover the relationship between the changes in beta amyloid protein (Aβ) levels in blood and brain and the expression of ptk2b in Aβ-induced cognitive dysfunction mice. A total of 64 3-month-old C57BL/6J mice were divided randomly into the experimental group and control group. All mice underwent the intracerebroventricular (i.c.v.) intubation. Mice in the experimental group received the i.c.v. infusion of oligomeric Aβ
Alzheimer Disease ; Amyloid beta-Peptides/metabolism* ; Animals ; Brain ; Cognitive Dysfunction/chemically induced* ; Disease Models, Animal ; Focal Adhesion Kinase 2 ; Hippocampus/metabolism* ; Mice ; Mice, Inbred C57BL ; Peptide Fragments

Objective: In the present study, the ABCA1 was used as a label to capture specific exosomes, the level of ABCA1-labeled exosomal microRNA-135a (miR-135a) was evaluated for the diagnosis of Alzheimer's disease (AD), especially in patients with early stages of AD. Methods: This is a preliminary research focused on the levels of ABCA1 in WBCs, RBCs, HT-22 cells, and neuron cells. The diagnostic value of ABCA1-labeled exosomal miR-135a was examined using the CSF and serum of APP/PS1 double transgenic mice, and 152 patients with SCD, 131 patients with MCI, 198 patients with DAT, and 30 control subjects. Results: The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs ( Conclusion This study outlines a method to capture specific exosomes and detect them using immunological methods, which is more efficient for early diagnosis of AD.
ATP Binding Cassette Transporter 1/cerebrospinal fluid* ; Aged ; Aged, 80 and over ; Alzheimer Disease/cerebrospinal fluid* ; Animals ; Biomarkers/cerebrospinal fluid* ; Cell Line ; Cognitive Dysfunction/cerebrospinal fluid* ; Erythrocytes/metabolism* ; Exosomes ; Female ; Humans ; Leukocytes/metabolism* ; Male ; Mice, Transgenic ; MicroRNAs/blood* ; Neurons/metabolism*

Objective To explore the effect of dexmedetomidine(Dex)on sevoflurane-induced cognitive impairment in neonatal rats through Wnt signaling pathway. Methods Sixty 7-day-old SD rats were assigned into five groups:control group(without any intervention),Dex group(intraperitoneal injection of 25 μg/kg Dex),sevoflurane group(3% sevoflurane treatment for 4 hours),sevoflurane+Dex group(inhalation of 3% sevoflurane after injection of 25 μg/kg Dex for 4 hours),and sevoflurane+Dex+Wnt inhibitor group(Wnt inhibitor XAV393 and 25 μg/kg Dex were injected and 3% sevoflurane was inhaled for 4 hours).Three weeks later,Morris water maze was used to detect the cognitive function;TdT-mediated dUTP nick end labeling(TUNEL)staining was performed to detect the apoptosis of hippocampal neurons;neuronal nuclei (NeuN) staining was conducted to detect the survival of hippocampal neurons;Western blot was carried out to detect the expression of apoptosis-related proteins.The expression of the factors involved in Wnt/GSK-3β/β-catenin signaling pathway was detected by fluorescence quantitative polymerase chain reaction,and Western blot. Results Compared with the control group,there was no significant difference in the escape latency of Dex group(t=0.304,P=0.768);the escape latency in sevoflurane group(t=5.823,P=0.002),sevoflurane+Dex group(t=3.188,P=0.010),and sevoflurane+Dex+Wnt inhibitor group(t=5.784,P=0.002)was significantly prolonged.Compared with that in the sevoflurane group,the escape latency in sevoflurane+Dex group(t=3.646,P=0.005)was significantly shortened.Compared with that in sevoflurane+Dex group,the escape latency in sevoflurane+Dex+Wnt inhibitor group(t=3.296,P=0.008)was prolonged.Compared with that in the control group,the times of crossing platform in sevoflurane group(t=5.179, P=0.004),sevoflurane+Dex group(t=2.309,P=0.043),and sevoflurane+Dex+Wnt inhibitor group(t=3.871, P=0.003)decreased.Compared with that in sevoflurane group,the times of crossing platform in sevoflurane+Dex group(t=3.296,P=0.008)significantly increased.Compared with that in sevoflurane+Dex group,the times of crossing platform in sevoflurane+Dex+Wnt inhibitor group(t=2.361, P=0.041)reduced.Compared with the control group,there was no significant difference in the number of apoptotic cells in Dex group(t=1.920,P=0.127),and the number of apoptotic cells in sevoflurane group,sevoflurane+Dex group,and sevoflurane+Dex+Wnt inhibitor group increased by 16%(t=13.436,P=0.002),5%(t=7.752, P=0.001),and 11.5%(t=12.612,P=0.002),respectively.Compared with that in the sevoflurane group,the number of apoptotic cells in sevoflurane+Dex group and sevoflurane+Dex+Wnt inhibitor group decreased by 11%(t=8.521,P=0.002)and 5.5%(t=3.123,P=0.036),respectively.Compared with that in the sevoflurane+Dex group,the number of apoptotic cells in sevoflurane+Dex+Wnt inhibitor group increased by 6.5%(t=6.250,P=0.003).Compared with that in the control group,the number of positive cells in 0.15 mm
Animals ; Animals, Newborn ; Cognitive Dysfunction/chemically induced* ; Dexmedetomidine/pharmacology* ; Glycogen Synthase Kinase 3 beta ; Rats ; Rats, Sprague-Dawley ; Sevoflurane/toxicity* ; Wnt Signaling Pathway ; beta Catenin/metabolism*