PSD-95 Levels Research Articles

Social-Single Prolonged Stress affects contextual fear conditioning in male and female Wistar rats: Molecular insights in the amygdala

Stress exposure can lead to post-traumatic stress disorder (PTSD) in male and female rats. Social-Single Prolonged Stress (SPS) protocol has been considered a potential PTSD model. This study aimed to pharmacologically validate the Social-SPS as a PTSD model in male and female rats. Male and female Wistar rats (60-day-old) were exposed to Social-SPS protocol and treated with fluoxetine (10 mg/Kg) or saline solution intraperitoneally 24 h before euthanasia. Two cohorts of animals were used; for cohort 1, male and female rats were still undisturbed until day 7 post-Social-SPS exposure, underwent locomotor and conditioned fear behaviors, and were euthanized on day 9. Animals of cohort 2 were subjected to the same protocol but were re-exposed to contextual fear behavior on day 14. Results showed that fluoxetine-treated rats gained less body weight than control and Social-SPS in both sexes. Social-SPS effectively increased the freezing time in male and female rats on day eight but not on day fourteen. Fluoxetine blocked the increase of freezing in male and female rats on day 8. Different mechanisms for fear behavior were observed in males, such as Social-SPS increased levels of glucocorticoid receptors and Beclin-1 in the amygdala. Social-SPS was shown to increase the levels of NMDA2A, GluR-1, PSD-95, and CAMKII in the amygdala of female rats. No alterations were observed in the amygdala of rats on day fourteen. The study revealed that Social-SPS is a potential PTSD protocol applicable to both male and female rats.

Human umbilical cord blood mesenchymal stem cells mediate microglia activation and improve anxiety-like behavior in MIA-induced offspring of schizophrenic rats

Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.

Effect of South Sulawesi Propolis in Sevoflurane Anesthesia-Induced Rat Model During Weaning Period: Study Levels of IL-6, TNF⍺, IL-10, and PSD-95 of the Prefrontal Cortex

Background: A recent study discovered that exposure to the anesthetic gas sevoflurane in the early years of life can impact cognitive function. Objectives: This study aims to investigate the effects of prolonged and repeated exposure to sevoflurane during the weaning period and whether the administration of propolis, a well-known herbal substance with anti-inflammatory properties, has a beneficial effect on inflammation and synaptic markers of the prefrontal cortex area, as well as its effect on spatial working memory function. Methods: We utilized Sprague Dawley rats aged 21 days (P21), divided into three groups: Control, sevoflurane, and sevoflurane with propolis. The exposure to sevoflurane (3%) was conducted three times for 2 hours each at P21, P23, and P25. Propolis treatments were administered orally, starting from the first day of exposure to sevoflurane until the rats were sacrificed (P25 or P51). Analyses of IL-6, TNF-alpha, IL-10, PSD-95 levels were performed using ELISA at P25 and P51, while spatial working memory was measured using the spontaneous Y-maze at P51. Results: Exposure to sevoflurane during the weaning period had no effect on IL-6, TNF-alpha, IL-10, and PSD-95 levels of the prefrontal cortex, nor on working memory function. Similarly, the administration of propolis did not have any beneficial effect on these parameters. Conclusions: Prolonged and repeated exposure to sevoflurane during the weaning period did not induce neuroinflammation conditions that also did not affect synaptic markers and working memory function. Further studies are required to identify a dose of sevoflurane that causes detrimental effects on memory function, neuroinflamation and synaptic marker and further to explore the beneficial effects of propolis on this condition.

Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aβ) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aβ1-42 and Aβ plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aβ1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aβ plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aβ levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.

Antidepressant-like effects of hyperoside on chronic stress-induced depressive-like behaviors in mice: Gut microbiota and short-chain fatty acids

BackgroundThe antidepressant effect of hyperoside (HYP), which is the main component of Hypericum perforatum, is not established. This study aimed to determine the effects of HYP on depression. MethodsThe antidepressant-like effect of HYP was studied in mice induced by chronic restraint stress (CRS). The effects of HYP on behavior, inflammation, neurotransmitters, gut microbiota, and short-chain fatty acids (SCFAs) were studied in CRS mice. ResultsHYP improved depressive-like behavior in mice induced by CRS. Nissl staining analysis showed that HYP improved neuronal damage in CRS mice. Western blot (WB) analysis showed that HYP increased the expression levels of BDNF and PSD95 in the hippocampus of CRS mice. The results of ELISA showed that HYP down-regulated the expression levels of IL-6, IL-1β, TNF-α, and CORT in the hippocampus, blood, and intestinal tissues of mice and up-regulated the expression levels of 5-HT and BDNF. Hematoxylin and eosin (HE) staining results indicate that HYP can improve the intestinal histopathological injury of CRS mice. The results of 16S rRNA demonstrated that HYP attenuated the dysbiosis of the gut microbiota of depressed mice, along with altering the concentration of SCFAs. LimitationsIn the present study, direct evidence that HYP improves depressive behaviors via gut microbiota and SCFAs is lacking, and only female mice were evaluated, which limits the understanding of the effects of HYP on both sexes. ConclusionsHYP can improve CRS-induced depressive-like behaviors in mice, which is associated with regulating the gut microbiota and SCFAs concentration.

Neurodevelopmental disorders and the role of PSD-95: Understanding pathways and pharmacological interventions

Neurodevelopmental disorders (NDDs) are often linked to disruption in brain development and present challenges for affected individuals in achieving their cognitive, emotional, and motor developmental milestones. NDDs encompass a spectrum of conditions, including autism spectrum disorder (ASD), schizophrenia (SCZ), attention-deficit hyperactivity disorder (ADHD), and epilepsy. The unequivocal diagnosis of an NDD is often challenging due to overlapping signs and symptoms across different conditions. Synaptic plasticity, the activity-driven modification of synaptic strength and efficacy, plays a crucial role in brain network formation and organization and is frequently altered in NDDs. Here, we explore the multifaceted roles of postsynaptic density-95 kDa (PSD-95) in NDDs. Psd-95 is a scaffolding protein belonging to the membrane-associated guanylate kinases (MAGUKs) family, located at the core of synapses, and is central to synaptic plasticity. Dysregulation of PSD-95 is linked to various neuropsychiatric disorders. In SCZ, decreased PSD-95 expression affects synaptic plasticity, thereby impacting learning and memory. Genes associated with ASD interact with PSD-95, and its removal in mice leads to ASD-like behavioral abnormalities. Furthermore, PSD-95 is implicated in ADHD, where its modulation influences neurotransmission. Medications used in NDD treatment, such as antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs), can alter PSD-95 levels, potentially influencing synapse formation. Alpha-2 adrenergic agonists might enhance synaptic integrity by impacting PSD-95. Alternative pharmacotherapies such as memantine, allopurinol, and ketamine, all influencing PSD-95 to a certain extent, hold promise in managing NDDs. Understanding the role of PSD-95 in these disorders can deepen our biological comprehension and pave the way for targeted therapies. Specifically, exploring how PSD-95 affects synaptic plasticity and dendritic spine development could uncover opportunities for repurposing drugs to treat NDDs associated with mutations in the DLG4 gene encoding PSD-95.

Dendrobine Ameliorates Alzheimer's Disease-like Pathology and Cognitive Decline in 3 × Tg-AD Mice.

Previous studies have shown that Dendrobium nobile Lindl. alkaloids (DNLAs) have neuroprotective effects in several Alzheimer's disease (AD) models. Dendrobine (DDB) is one of the monomer components with the highest content in DNLAs. However, the effects of DDB on cognitive impairments in AD remain unknown. In this study, we investigated the efficacy of DDB in 3 × Tg-AD mice to determine whether DDB was a key component of the anti-AD effect of DNLAs. Five-month mice were intragastrically administrated with DDB (10 and 20 mg/kg/d) or DNLAs (20 mg/kg/d) for seven consecutive months, and the effects of DDB and DNLAs were evaluated at twelve months. The results revealed that 3 × Tg-AD mice treated with DDB showed enhanced nesting ability. DDB also effectively rescued spatial learning and memory deficits in 3 × Tg-AD mice. Meanwhile, DDB treatment prevented the loss of dendritic spine density, with increased expression levels of synaptophysin, PSD95, and NCAM in the hippocampus. Finally, DDB ameliorated the increase in APP, sAPPβ, CTF-β, and β-amyloid peptides, accompanied by the promotion of GSK phosphorylation at the Ser9 site, thereby reducing hyperphosphorylated tau levels. As the active component of DNLA, DDB can preserve cognitive function, alleviate neuronal and synaptic defects, and improve APP/tau pathology in 3 × Tg-AD mice.

Qingzhuan dark tea Theabrownin alleviates hippocampal injury in HFD-induced obese mice through the MARK4/NLRP3 pathway

BackgroundFeeding on a high-fat diet (HFD) results in obesity and chronic inflammation, which may have long-term effects on neuroinflammation and hippocampal injury. Theabrownin, a biologically active compound derived from the microbial fermentation of Qingzhuan dark tea, exhibits anti-inflammatory properties and lipid-lowering effects. Nevertheless, its potential in neuroprotection has yet to be investigated. Consequently, this study aims to investigate the neuroprotective effects of Theabrownin extracted from Qingzhuan dark tea, as well as its potential therapeutic mechanisms. MethodsMale C57 mice were subjected to an 8-week HFD to induce obesity, followed by oral administration of Theabrownin from Qingzhuan dark tea. Lipid levels were detected by Elisa kit, hippocampal morphological damage was evaluated by HE and Nissl staining, and the expression levels of GFAP, IBA1, NLRP3, MARK4, and BAX in the hippocampus were detected by immunofluorescence (IF), and protein expression levels of NLRP3, MARK4, PSD95, SYN1, SYP, and Bcl-2 were detected by Western Blot (WB). ResultsTheabrownin treatment from Qingzhuan dark tea prevents alterations in body weight and lipid levels in HFD-fed mice. Furthermore, Theabrownin decreased hippocampal morphological damage and reduced the activation of astrocytes and microglia in HFD-fed mice. Moreover, Theabrownin decreased the expression of MARK4 and NLRP3 in HFD-fed mice. Besides, Theabrownin elevated the expression of PSD95, SYN1, and SYP in HFD-fed obese mice. Finally, Theabrownin prevented neuronal apoptosis, reduced the expression of BAX, and increased the expression of Bcl-2 in HFD-fed obese mice. ConclusionsIn summary, our current study presents the first demonstration of the effective protective effect of Theabrownin from Qingzhuan dark tea against HFD-induced hippocampal damage in obese mice. This protection may result from the regulation of the MARK4/NLRP3 signaling pathway, subsequently inhibiting neuroinflammation, synaptic plasticity, and neuronal apoptosis.

Enhanced meningeal lymphatic drainage ameliorates lipopolysaccharide-induced brain injury in aged mice

BackgroundSepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE.MethodsSepsis was established in male C57BL/6J mice by intraperitoneal injection of 5 mg/kg lipopolysaccharide, and the function of meningeal lymphatic drainage was assessed. Adeno-associated virus 1-vascular endothelial growth factor C (AAV1-VEGF-C) was injected into the cisterna magna to induce meningeal lymphangiogenesis. Ligation of deep cervical lymph nodes (dCLNs) was performed to induce pre-existing meningeal lymphatic dysfunction. Cognitive function was evaluated by a fear conditioning test, and inflammatory factors were detected by enzyme-linked immunosorbent assay.ResultsThe aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment.ConclusionThe meningeal lymphatic drainage is damaged in sepsis, and pre-existing defects in this drainage system exacerbate SAE-induced neuroinflammation and cognitive dysfunction. Promoting meningeal lymphatic drainage improves SAE. Manipulation of meningeal lymphangiogenesis could be a new strategy for the treatment of SAE.

MR1/MAIT Cell Axis Impacts Innate Immunity and Synaptic Proteins in 5XFAD Mice

Background:
 Amyloid beta (Aβ)-induced synaptic dysfunction and inflammation are features of Alzheimer’s disease (AD). One contributor to inflammation is mucosal-associated invariant T (MAIT) cells, an innate T cell that recognizes antigens presented by the MR1 molecule. Previously, we found increased MR1 expression in microglia near plaques and the loss of MR1/MAIT cell axis slowed the progression of Aβ pathology. This study aimed to determine contributions of the MR1/MAIT cell axis to immunity and synaptic proteins in the 5XFAD AD model mouse.
 Methods:
 We crossed 5XFAD mice with MR1-deficient mice (which lack MR1 and MAIT cells). At 2-, 4-, 6-, and 8-months of age, hippocampal and cortical brain tissue from wild-type, MR1KO, 5XFAD, and 5XFAD/MR1KO mice were analyzed by Western blot. Protein levels were analyzed with antibodies against GFAP (astrocytes), complement C3, and postsynaptic density protein (PSD)95. Additionally, Novel Object Recognition, Open Field, and Barnes Maze behavioral tests were performed in the 5XFAD mice to measure memory deficits.
 Results:
 Region-specific results were obtained for the hippocampus and cortex. The expression levels of PSD95 and C3 were significantly upregulated in the hippocampus of 5XFAD/MR1KO compared to 5XFAD mice at 6-8 months of age; in the cortex, GFAP levels were also significantly increased in 5XFAD/MR1KO mice. Finally, compared to wildtype C57BL/6 mice, 5XFAD mice showed memory deficits.
 Conclusions and Potential Impact:
 Approximately 6.7 million Americans are living with AD. This number is expected to double by 2050. Without any currently demonstrated therapy against AD, there is a need for therapeutic target(s) as part of novel treatment paradigms. Our results demonstrate an impact of the MR1/MAIT cell axis on postsynaptic proteins and consequent AD pathology. Thus, understanding the contribution of this axis could help reveal the role of innate immunity in AD and potentially serve as a future therapeutic target in AD patients.

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice.

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/β-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

Effects of esketamine on depression-like behavior and dendritic spine plasticity in the prefrontal cortex neurons of spared nerve injury-induced depressed mice.

The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression.

Chlorogenic Acid Mitigates Ferroptosis by Activating the Nrf2/GPX4 Pathway through Keap1 Blockade in Vascular Dementia Rats

Chlorogenic acid (CGA) is a dietary phenolic acid widely distributed in daily food and plants, but its role in vascular dementia (VaD) is still unclear. Hence, this study aimed to investigate whether CGA could rescue cognitive impairment in VaD, providing a new option for drug discovery. Novel object recognition and Morris water maze experiments revealed that CGA enhanced the learning and memory abilities in VaD rats. Nissl staining, Western blot, and transmission electron microscopy results demonstrated that CGA inhibited neuronal loss in the hippocampal CA1 region of VaD rats, increased the expression of synaptic‐related markers SYP and PSD95, thickened the postsynaptic density, and suppressed mitochondrial ridge rupture in neurons. GSH detection, MDA detection, and Western blot experiments indicated that CGA alleviated hippocampal GSH reduction and MDA elevation and increased the protein levels of GPX4 and SLC7A11. Cell activity, ROS detection, lipid peroxidation detection, intracellular Fe2+ level detection, GSH detection, and Western blot revealed that CGA inhibited the increase of intracellular Fe2+, ROS, and lipid peroxidation induced by OGD in PC12 cells, mitigated GSH reduction, and increased the protein levels of GPX4, SLC7A11, SYP, and PSD95. Western blot and immunofluorescence staining showed that CGA increased the expression of pSer40‐Nrf2 in the hippocampal tissue of VaD rats and PC12 cells, promoting Nrf2 nuclear translocation. Knockdown of Nrf2 prevented CGA from rescuing ferroptosis and synaptic damage induced by OGD in PC12 cells, as well as Nrf2 pathway activation. Molecular docking analysis suggested that CGA competitively bound to the Kelch domain of Keap1 with Nrf2 and then promoted Nrf2 release and activated downstream signaling pathways. In conclusion, our study suggests that CGA may activate the Nrf2 signaling pathway by disrupting the interaction between Nrf2 and Keap1 proteins, thereby inhibiting hippocampal neuronal ferroptosis and synaptic damage and ameliorating cognitive impairment in VaD. Practical Applications. Vascular dementia (VaD) stands as the second most prevalent type of dementia following Alzheimer’s disease. However, there is no effective clinical treatment drug available, and its pathogenic mechanisms remain elusive. This study proposed that CGA might activate the Nrf2‐GPX4 signaling pathway by competitively binding to Keap1, thereby attenuating hippocampal neuronal ferroptosis and synaptic damage and consequently ameliorating cognitive impairment in VaD. Our study may provide a novel option for drug research and development for VaD.

Ketogenic diet attenuates cognitive dysfunctions induced by hypoglycemia via inhibiting endoplasmic reticulum stress-dependent pathways.

Hypoglycemia can potentially cause severe damage to the central nervous system. The ketogenic diet (KD), characterized by high-fat and extremely low-carbohydrate content, can modulate homeostasis and nutrient metabolism, thereby influencing body health. However, the effects and underlying mechanisms of KD on hypoglycemia-induced brain injury have not been thoroughly investigated. We aimed to explore the modulating effects of KD on cognitive functions and elucidate the underlying mechanisms. In this study, one-month-old mice were fed with KD for 2 weeks, and the changes in the gut microbiota were detected using the 16S rRNA gene amplicon sequencing method. The hypoglycemic model of mice was established using insulin, and the potential protective effect of KD on hypoglycemia-induced brain injury in mice was evaluated through immunofluorescence staining, western blotting, transmission electron microscopy, and Golgi staining. Our results showed that the intestinal flora of Dorea increased and Rikenella decreased in KD-fed mice. KD can not only alleviate anxiety-like behavior induced by hypoglycemia, but also increase the proportion of mushroom dendritic spines in the hippocampus by modulating changes in the gut microbiota. KD regulated synaptic plasticity by increasing the levels of SPN, PSD95, and SYP, which relieve cognitive impairment caused by hypoglycemia. Moreover, KD can promote the proliferation and survival of adult neural stem cells in the hippocampus, while reducing apoptosis by suppressing the activation of the IRE1-XBP1 and ATF6 endoplasmic reticulum stress pathways in mice with hypoglycemia. This study provides new evidence for demonstrating that KD may alleviate cognitive dysfunctions caused by hypoglycemia by modulating the gut microbiota.

Kaempferol improves Pb-induced cognitive impairments via inhibiting autophagy

Kaempferol (Kam) is a flavonoid antioxidant found in fruits and vegetables, which was discovered as neuroprotective antioxidants. Lead (Pb), an environmental pollution, could induce learning and memory deficits. Nevertheless, little is known about the mechanisms underlying Kam actions in Pb-induced learning and memory deficits. In this study, we investigated the effects of Kam on Pb-induced cognitive deficits. Pb-exposed rats were treated with 50 mg/kg Kam from postnatal day (PND) 30 to PND 60. Then, Y-maze and Morris water maze have been used to detect the spatial memory in all groups of rats. Hematoxylin and eosin (HE) staining and Nissl staining were used to analyze the neuronal structure damages. The results found Kam treatment improved the learning and memory ability and alleviated hippocampal neuronal pathological damages. Besides, Kam could significantly reverse the synaptic transmission related protein expression including PSD95 and NMDAR2B. Further research found that Kam downregulated autophagy markers, P62, ATG5, Beclin1, and LC3-II. Furthermore, 3-MA, autophagy inhibitor, increased the levels of NMDAR2B and PSD95 in Pb-induced PC12 cells, indicating Kam alleviated Pb-induced neurotoxicity through inhibiting autophagy activation. Our results showed that Kam could ameliorate Pb-induced cognitive impairments and neuronal damages by decreasing Pb-induced excess autophagy accumulation.

Aerobic exercise training improves memory function through modulation of brain-derived neurotrophic factor and synaptic proteins in the hippocampus and prefrontal cortex of type 2 diabetic rats.

Defective insulin signaling in the brain may disrupt hippocampal neuroplasticity resulting in learning and memory impairments. Thus, this study investigated the effect of aerobic exercise training on cognitive function and synaptic protein markers in diabetic rats. Twenty male Wistar rats (200-250g), were fed on high-fat diet and received a low dose of streptozotocin (35mg/kg, i.p) to induce type 2 diabetes. Then diabetic animals were randomly divided into sedentary and training groups. The exercise training program was treadmill running at 27m/min for 60min/day for 8 weeks. One day after the last training session, Morris Water Maze (MWM) task was performed to evaluate spatial learning and memory. Then, the hippocamp and prefrontal cortex tissues were instantly dissected for immunoblotting assay of BDNF, GSK-3β, p-GSK-3β, P38, p-P38, ERK1/2, p-ERK1/2, heat shock protein-27 (HSP27), SNAP-25, synaptophysin, and PSD-95. Independent t-test analysis and two-way ANOVA was used to determine the differences under significance level of 0.05 using the 26th version of IBM SPSS statistical software. The results showed that aerobic exercise improved memory as assessed in the MWM task. Moreover, aerobic exercise up-regulated HSP27 and BDNF protein levels in the prefrontal cortex, and hippocampus coincided with robust elevations in SNAP25 and PSD-95 levels. Moreover, exercise reduced phosphorylated P38, while increased p-ERK1/2 and p-GSK-3β (p). Our findings suggest that aerobic exercise may debilitate the harmful effects of diabetes on the cognitive function possibly through enhancing synaptic protein markers.

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia.

This study aimed to evaluate the efficacy and treatment mechanism of platelet-rich plasma (PRP) and neural crest-derived epidermal stem cells (ESCs) in their administration alone and combination in vascular dementia (VaD) model by two-vessel occlusion (2VO). Methods. Sixty-six rats were divided into six groups: the control, sham, 2VO + vehicle, 2VO + PRP, 2VO + ESC, and 2VO + ESC + PRP. The treated groups received 1 million cells on days 4, 14, and 21 with or without 500 µl PRP (twice a week) after 2VO. The memory performance and anxiety were evaluated by behavioral tests including open field, passive avoidance, and Morris water maze. The basal-synaptic transmission (BST) and long-term potentiation (LTP) were assessed through field-potential recordings of the CA1. The mRNA expression levels of IGF-1, TGF-β1, PSD-95, and GSk-3β were measured in the rat hippocampus by quantitative reverse transcription polymerase chain reaction. Results. The results demonstrated impaired learning, memory, and synaptic plasticity in the 2VO rats, along with a significant decrease in the expression of IGF-1, TGF-β1, PSD-95, and upregulation of GSK-3β. Treatment with ESC alone and ESC + PRP showed similar improvements in spatial memory and LTP induction, with associated upregulation of PSD-95 and downregulation of GSK-3β. However, only the ESC + PRP group showed recovery in BST. Furthermore, combination therapy was more effective than PRP monotherapy for LTP and memory. Conclusions. The transplantation of ESC showed better effects than PRP alone, and combination therapy increased the treatment efficacy with the recovery of BST. This finding may be a clue for the combination therapy of ESC and PRP for VaD.

Effects of Cyfluthrin Exposure on Neurobehaviour, Hippocampal Tissue and Synaptic Plasticity in Wistar Rats.

This experiment was conducted to study the effects of Cyfluthrin (Cy) exposure on neurobehaviour, hippocampal tissue and synaptic plasticity in Wistar rats. First, it was found that high-dose Cy exposure could cause nerve injury, resulting in symptoms such as deficits in learning and memory ability, spatial exploration and autonomic motor function. Moreover, it was found that medium- and high-dose Cy exposure could cause an abnormal release of the neurotransmitter Glu. Second, brain tissue pathology showed that the middle and high doses of Cy caused tissue deformation, reduced the number of hippocampal puramidal cells, caused a disorder of these cells, decreased the number of Nissl bodies, and caused pyknosis of the hippocampal cell nuclear membrane and serious damage to organelles, indicating that exposure to these doses of Cy may cause hippocampal tissue damage in rats. Third, as the exposure dose increased, morphological changes in hippocampal synapses, including blurred synaptic spaces, a decreased number of synaptic vesicles and a decreased number of synapses, became more obvious. Moreover, the expression levels of the key synaptic proteins PSD-95 and SYP also decreased in a dose-dependent manner, indicating obvious synaptic damage. Finally, the study found that medium and high doses of Cy could upregulate the expression of A2AR in the hippocampus and that the expression levels of inflammatory factors and apoptosis-related proteins increased in a dose-dependent manner. Moreover, the expression of A2AR mRNA was correlated with neurobehavioural indicators and the levels of inflammatory factors, synaptic plasticity-related factors and apoptosis-related factors, suggesting that Cy may cause nerve damage in rats and that this effect is closely related to A2AR.

Microglial deletion of C1q rescues AD cognitive decline and synaptic loss

AbstractBackgroundThe complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies have demonstrated constitutive deletion of the classical initiator protein, C1q, reduces pathology and synaptic loss in AD mouse model. As it is now known that microglia are the primary producers of C1q in the brain, the main objective of this study was to determine if microglial specific deletion of C1q would rescue cognitive impairment and synaptic loss in AD.MethodC1qaFLlFL:CX3CR1Cre (designated C1qΔMG)mice, which experience tamoxifen‐independent deletion of microglial C1q by 2 months of age, were crossed to Arctic: C1qaFl/Fl: mice to generate WT and Artic mice with and without the CX3CR1Cre transgene. At 10 months of age, mice underwent behavioral testing of hippocampal dependent spatial memory, including object location memory (OLM) and spatial reference Y‐maze. Tissue was collected at the end of testing and immunostained for pre (VGlut1) and post (PSD95) synaptic makers and Z‐stacks using superresolution microscopy in the CA1 of the hippocampus were obtained. The density of pre‐ and post‐synaptic puncta and their colocalization was assessed using IMARIS.ResultWhile both male and female Arctic mice displayed a significant impairment in long‐term memory, as assessed by OLM, microglial deletion of C1q rescued cognitive deficits in male but not female Arctic mice. Male Arctic C1qΔMGmice also performed better on Y‐maze testing than Arctic controls. Similar sex‐dependent results were observed in synaptic density. Female Arctic C1qΔMG mice displayed reduced levels of PSD95 and Vglut1 puncta compared to female Arctic mice, as well as a trending reduction in colocalization. In contrast, male Arctic C1qΔMG mice displayed increased levels of PSD95, trending reductions in VGlut1 compared to male Arctic controls, and trending increases in synaptic colocalization, suggesting an increase in functional synapses in the male mouse.ConclusionDeletion of C1q in microglia prior to amyloid plaque deposition protects against cognitive decline and synaptic loss in a greater extent in males than females.

Greater sensitivity of the hippocampus than the entorhinal cortex in response to western diet, manifested by accelerated neuroinflammation and neurodegeneration in the progression of Alzheimer’s disease

AbstractBackgroundThe western diet (WD), characterized by a combination of simple carbohydrates, saturated fatty acids and cholesterol, is known to induce metabolic syndrome and systemic inflammation. These peripheral disorders induce neuroinflammation and affect brain function, suggesting that WD may have a significant impact on Alzheimer’s disease (AD) progression (Więckowska‐Gacek et al., 2021). In this study we aimed to verify the hypothesis that WD feeding accelerates neuroinflammation, resulting in accelerated deposition of Aβ plaques, accelerated appearance of neurodegeneration markers and destabilization of neuronal cytoskeleton.MethodsTransgenic male mice expressing human APP with the Swedish mutation (APPswe) were divided into three age groups: 4‐ and 8‐month old animals (4M, 8M) represent early pre‐symptomatic stages of AD, while 12‐month old animals (12M) represent later stages of AD with visible amyloid pathology. The APPswe mice were fed standard or western diet from the 3rd month of age. The effect of WD on selected markers was analyzed in the hippocampus and entorhinal cortex by Western blotting and immunohistochemistry.ResultsCompared to control mice fed standard diet, WD feeding induced astrogliosis (GFAP) in the hippocampus as early as in 4M, followed by several changes in 8M such as activation of the pro‐inflammatory microglia (↑Iba1, ↓CD68, ↓P2RY12), a decrease in the level of TLR4, and the fluctuations of levels of pro‐inflammatory cytokines (IL‐1β, IL‐6). These changes in the hippocampus at 8M co‐occurred with enhanced production of Aβ plaques. Moreover, WD accelerated the processes associated with age‐related neurodegeneration (lower levels of PSD95 in 8M, and of NeuN in 12M). In the entorhinal cortex, the examined molecular changes appeared with a delay in time or not at all.ConclusionThese results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD which can accelerate development of AD pathology. Furthermore, the data demonstrate that, compared to the entorhinal cortex, the hippocampus is a brain structure that is generally more sensitive to the macronutrient composition characteristic of WD, manifested by accelerated neuroinflammation, amyloidopathy and neurodegeneration.Polish National Science Center grants: 2018/29/N/NZ7/01724, 2014/15/D/NZ4/04361