GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition.

AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Knowledge, Attitude, and Practice About Antibiotic Use and Antimicrobial Resistance Among Nursing Students in China: A Cross Sectional Study.

Purpose: The knowledge, attitude, and practices (KAP) concerning antibiotics by healthcare students have the potential impact on controlling antibiotic abuse and antimicrobial resistance (AMR) growth. This study aims to evaluate the levels and explore the associated factors with KAP on antibiotic use and AMR in Chinese nursing students. Methods: A cross-sectional survey using a self-administered questionnaire consisting of demographics and selected features and KAP on antibiotic use and AMR was conducted to measure KAP levels among nursing students at various universities in Hubei Province, China. The logistic regression analyses were performed to analyze the potential factors associated with the KAP. Results: The survey eventually included a total of 1959 nursing students. The mean scores for KAP were 57.89 ±26.32, 55.00 ±12.50, and 71.88 ±15.63, respectively. Regarding knowledge, 54.3% of participants were unaware that antibiotic was ineffective against viral infections. Regarding attitude, 36% of participants agreed that current antibiotic abuse existed; 96.2% of participants thought it necessary to set up a special course on antibiotics. Regarding practice, only 48.4% of participants usually purchased antibiotics with a prescription. Multivariable analyses indicated that lack of discussion on AMR in school courses was an independent risk factor against KAP, respectively. The main knowledge sources of antibiotic being outside the classroom was an independent risk factor related to knowledge and practice. The average score >80 points was an independent protective factor related to knowledge and practice. Conclusion: The KAP level on antibiotic use and AMR among Hubei nursing students was general and required further strengthening. Nursing students with risk factors should be prioritized in educational interventions. The findings of our study pointed out some directions for tailored interventions to improve the training on antibiotics.

P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior. METHODS: Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3ß inhibitor (LiCl) to the roles of CDK5 and GSK3ß in mediating ischemia-reperfusion-induced tau phosphorylation. RESULTS: Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD. CONCLUSION: These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.

BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.

BACE1 is essential for the generation of amyloid-ß (Aß) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aß accumulation.

Iron Chelation Remits Memory Deficits Caused by the High-Fat Diet in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer's disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-ß (Aß) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aß accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. OBJECTIVE: To explore the accurate role of HFD in the pathogenesis of AD. METHODS: Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls' Prussian blue staining, and ELISA were used. RESULTS: HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aß1-40 and Aß1-42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. CONCLUSION: These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies.

High Fat Diet Aggravates AD-Related Pathogenic Processes in APP/PS1 Mice.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder and negative lifestyle factors may contribute to its etiopathogenesis. Substantial evidence from humans and murine models reveals that Insulin Resistance (IR) associated with a high fat diet (HFD) increases the risk of developing AD and age-related amyloidogenesis. OBJECTIVE: The aim of the study was to corroborate and clarify the influence of HFD on amyloidogenesis and cognitive deficits in AD model mice. METHODS: We here show that a four months HFD-feeding increases IR in both the periphery and brain of APP/PS1 mice, which are used as AD models. Meanwhile, long-term HFD exacerbates cognitive defects and impairs dendritic integrity and expressions of synaptic proteins in APP/PS1 mice. Furthermore, HFD induces an increase in ß-secretase (BACE1) expression and a decrease in insulin-degrading enzyme (IDE) expression, resulting in ß-amyloid (Aß) accumulation. CONCLUSION: Our data suggest that long-term HFD, with the accompanying IR, promotes Aß toxicity and cognitive deficits, indicating that modifiable lifestyle hazards such as HFD-induced IR might contribute to AD pathogenesis.

Epigallocatechin-3-gallate Alleviates Cognitive Deficits in APP/PS1 Mice.

Alzheimer's disease (AD) shows cognitive impairments in clinic, which is multifactorial with different etiopathogenic mechanisms such as Aß deposition, neuroinflammation and neuronal dystrophy involved. Therefore, multi-targets drugs with neuroprotective, anti-amyloidogenic and anti-inflammatory properties will be effective in AD treatment. Epigallocatechin-3-gallate (EGCG) possesses a broad spectrum of pharmacological activities in the prevention and treatment of multiple neurodegenerative diseases. In the present study, we showed that oral administration of EGCG (50 mg/kg) for 4 months significantly attenuated the cognitive deficits in APP/PS1 transgenic mice, which served as AD model. Moreover, EGCG induced an improvement in dendritic integrity and expression levels of synaptic proteins in the brain of APP/PS1 mice. And EGCG exerted obvious anti-inflammatory effects, which was manifested by alleviating microglia activation, decreasing pro-inflammatory cytokine (IL-1ß) and increasing anti-inflammatory cytokines (IL-10, IL-13). Furthermore, ß-amyloid (Aß) plaques were markedly reduced in the hippocampus of 6-month old APP/PS1 mice after EGCG treatment. In conclusion, these findings indicate that EGCG improves AD-like cognitive impairments through neuroprotective, anti-amyloidogenic and anti-inflammatory effects, thus is a promising therapeutic candidate for AD.

Acute stress enhances learning and memory by activating acid-sensing ion channels in rats.

Acute stress has been shown to enhance learning and memory ability, predominantly through the action of corticosteroid stress hormones. However, the valuable targets for promoting learning and memory induced by acute stress and the underlying molecular mechanisms remain unclear. Acid-sensing ion channels (ASICs) play an important role in central neuronal systems and involves in depression, synaptic plasticity and learning and memory. In the current study, we used a combination of electrophysiological and behavioral approaches in an effort to explore the effects of acute stress on ASICs. We found that corticosterone (CORT) induced by acute stress caused a potentiation of ASICs current via glucocorticoid receptors (GRs) not mineralocorticoid receptors (MRs). Meanwhile, CORT did not produce an increase of ASICs current by pretreated with GF109203X, an antagonist of protein kinase C (PKC), whereas CORT did result in a markedly enhancement of ASICs current by bryostatin 1, an agonist of PKC, suggesting that potentiation of ASICs function may be depended on PKC activating. More importantly, an antagonist of ASICs, amiloride (10 µM) reduced the performance of learning and memory induced by acute stress, which is further suggesting that ASICs as the key components involves in cognitive processes induced by acute stress. These results indicate that acute stress causes the enhancement of ASICs function by activating PKC signaling pathway, which leads to potentiated learning and memory.

Hyperoside protects against chronic mild stress-induced learning and memory deficits.

Hyperoside (quercetin-3-O-b-d-galactosidepyranose) is a plant-derived flavonoid mainly found in fruits, fruit juices (most notably flavanols, flavanones, and anthocyanins) and Chinese traditional medicines. It has been applied to relieve pain and improve cardiovascular functions in clinic. However, the effects of hyperoside on cognitive impairment induced by chronic stress and the underlying molecular mechanisms remain unclear. In the current study, we used chronic mild stress (CMS) rats to investigate the effects of hyperoside on learning and memory and further explore the possible mechanisms. Our results demonstrated that hyperoside reduced the escape latency and the swimming distance of CMS rats in Morris water maze test and reversed depressive symptoms in forced swim test (FST) and sucrose preference test. In addition, hyperoside increased the expression of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS rats without influencing the corticosterone (CORT) level in blood plasma. Furthermore, K252a, an inhibitor of the BDNF receptor TrkB, prevented the protective effects of hyperoside on learning and memory in CMS rats. Taken together, these results indicate that hyperoside reverses the cognitive impairment induced by CMS, which is associated with the regulation of BDNF signaling pathway.