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Long-term use of sevoflurane, an inhalation anesthetic, could negatively impact cognitive function. Current studies have suggested that cognitive impairment induced by sevoflurane may be associated with neuroinflammation. Sestrin2 (SESN2), which belongs to a family of stress-inducible genes, has been reported to exert neuroprotective effects against brain injury. However, its role and underlying mechanisms in sevoflurane-induced cognitive dysfunction in aged rats remain unknown. A sevoflurane-induced aging rat injury model with or without SESN2 overexpression was constructed. The learning and memory abilities of rats were evaluated by the MWM test. ELISA assay and qRT-PCR were conducted to analyze the level of pro-inflammatory factors in the hippocampus. Levels of oxidative stress markers were measured by DHE staining or kit methods. Neuronal apoptosis in the hippocampus was detected using TUNEL assay. Expression of proteins were analyzed by western blot. Sevoflurane exposure caused elevated protein level of SESN2 in hippocampus and cognitive impairment of aged rats. Importantly, overexpression of SESN2 alleviated sevoflurane-induced cognitive dysfunction and inhibited the production of pro-inflammatory factors, oxidative stress, and neuronal apoptosis in the hippocampus. Furthermore, SESN2 overexpression suppressed NLRP3 inflammasome activation induced by sevoflurane. These findings suggested that SESN2 could exert neuroprotective against sevoflurane-induced nerve injury of aged rats through anti-oxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a prevalent central nervous system complication predominantly observed in elderly patients. Sevoflurane, a general anaesthetic agent, has been implicated in the development of POCD, yet the underlying regulatory mechanisms potentially involving Sestrin1 (SESN1), a stress‐responsive protein that plays a critical role in cellular homeostasis and protection against stress‐induced damage, including oxidative stress and DNA damage, remain elusive. This study endeavoured to elucidate the impact of SESN1 on sevoflurane‐induced cognitive impairment in rats. Employing a model in which SESN1 was transfected into SD male rats and cognitive dysfunction was induced by sevoflurane. The Morris Water Maze test was used for behavioural evaluation, Enzyme‐Linked Immunosorbent Assay, Western blotting and immunofluorescence were applied to assess the influence of SESN1 on the inflammatory response and mitophagy in the rat hippocampus. The study further aimed to uncover the putative mechanism by which SESN1, through SIRT1, might modulate cognitive function. Concurrently, levels of malondialdehyde, superoxide dismutase and mitochondrially produced ATP within the rat hippocampus were quantified. Experimental outcomes suggested that SESN1 overexpression significantly mitigated the deleterious effects of sevoflurane anaesthesia, ameliorated neuroinflammation and inflammasome activation, modified mitochondrial function and facilitated mitophagy. Additionally, SESN1, via the activation of SIRT1, may suppress inflammasome activation and mitochondrial dysfunction. Collectively, these findings underscore SESN1's integral role in counteracting sevoflurane‐induced cognitive impairment, impeding inflammasome activation, enhancing mitochondrial function and fostering mitophagy, which appear to be intricately linked to SESN1‐mediated SIRT1 activation. SESN1 is a novel therapeutic target for POCD, potentially advancing neuroprotective strategies in clinical settings. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and post-stroke cognitive impairment (PSCI) are the leading causes of progressive dementia related to neurodegenerative and cerebrovascular injuries in elderly populations. Despite decades of research, patients with these conditions still lack minimally invasive, low-cost, and effective diagnostic and treatment methods. MicroRNAs (miRNAs) play a vital role in AD and PSCI pathology. As they are easily obtained from patients, miRNAs are promising candidates for the diagnosis and treatment of these two disorders. In this study, we performed complete sequencing analysis of miRNAs from 24 participants, split evenly into the PSCI, post-stroke non-cognitive impairment (PSNCI), AD, and normal control (NC) groups. To screen for differentially expressed miRNAs (DE-miRNAs) in patients, we predicted their target genes using bioinformatics analysis. Our analyses identified miRNAs that can distinguish between the investigated disorders; several of them were novel and never previously reported. Their target genes play key roles in multiple signaling pathways that have potential to be modified as a clinical treatment. In conclusion, our study demonstrates the potential of miRNAs and their key target genes in disease management. Further in-depth investigations with larger sample sizes will contribute to the development of precise treatments for AD and PSCI. [ABSTRACT FROM AUTHOR]

Background: Dementia and cognitive impairment can be attributed to genetic and modifiable factors. Considerable evidence emerged in modifiable factors and urgently requires standardized evaluation. We conducted an umbrella review to evaluate the strength and validity of the existing evidence.Methods: We searched PubMed, Embase, CINAHL and Cochrane Database of Systematic Reviews to identify relevant systematic reviews and meta-analyses of prospective studies regarding the associations of dementia and cognitive impairment with modifiable factors. For each association, we analyzed the summary effect size, 95 % confidence interval, 95 % prediction interval, heterogeneity, small study effect and excess significance bias. Mendelian randomization studies were descriptively reviewed further exploring the causality of the associations.Results: In total, 12,015 articles were identified, of which 118 eligible studies yielded 243 unique associations. Convincing evidence was found for associations of dementia and cognitive impairment with early-life education, midlife to late-life plasma glucose, BMI, atrial fibrillation, benzodiazepine use, and gait speed. Suggestive to highly suggestive evidence was found for that of midlife to late-life blood pressure, homocysteine, cerebrovascular diseases, hearing impairment, respiratory illness, anemia, smoking, alcohol consumption, diet, sleep, physical activity and social engagement. Among convincing evidence, Mendelian randomization studies verified causal relationships of education and plasma glucose with Alzheimer's disease.Limitations: Low quality of the studies included.Conclusions: Modifiable risk factors identified in this study, especially those with high-level evidence, should be considered in dementia prevention. Our results support a valuable rationale for future experimental designs to establish further evidence for the associations in larger populations. [ABSTRACT FROM AUTHOR]

Highlights • miR-132 was decreased in hippocampus and cortex of rats after chronic cerebral hypoperfusion (CCH). • miR-132 improved dementia susceptibility induced by 2VO. • miR-132 prevents CCH-induced learning and memory impairments by down-regulating the expression of Nav1.1 and Nav1.2. • Voltage-gated sodium channel alpha subunit 1(SCN1A) and voltage-gated sodium channel alpha subunit 2 (SCN2A) are the potential target genes of miR-132. Abstract Nav1.1 and Nav1.2 are the voltage-gated sodium channel alpha subunit1 and 2, encoded by the genes of SCN1A and SCN2A. Previous studies have shown that chronic cerebral hypoperfusion (CCH) could induce neuropathological and cognitive impairment and increased total Nav1.1 and Nav1.2protein levels, yet the detailed mechanisms are not fully understood. MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are involved in the regulation of dementia. miR-132 is known to play a key role in neurodegenerative disease. Here, we determined that miR-132 regulates Nav1.1 and Nav1.2 under CCH state. In this study, the expression of miR-132 was decreased in both the hippocampus and cortex of ratsfollowing CCH generated by bilateral common carotid artery occlusion (2VO). Lentiviral-mediated overexpression of miR-132 ameliorated dementia vulnerability induced by 2VO. At the molecular level, miR-132 repressed the increased protein expression of Nav1.1 and Nav1.2 in both the hippocampus and cortex induced by 2VO. MiR-132 suppressed, while AMO-miR-132 enhanced, the level of Nav1.1 and Nav1.2 in primary cultured neonatal rat neurons (NRNs) detected by both western blot analysis and immunofluorescence analysis. Results obtained by dual luciferase assay showed that overexpression of miR-132 inhibited the expression of Nav1.1 and Nav1.2 in human embryonic kidney 293 (HEK293T) cells. Additionally, binding-site mutation failed to influence Nav1.1 and Nav1.2, indicating that Nav1.1 and Nav1.2 are potential targets for miR-132. Taken together, our findings demonstrated that miR-132 protects against CCH-induced learning and memory impairments by down-regulating the expression of Nav1.1 and Nav1.2, and SCN1A and SCN2A are the target genes of miR-132. [ABSTRACT FROM AUTHOR]

Aggregation of amyloid protein (A and progressive loss of memory are the main characteristics of Alzheimer's disease (AD). It is noteworthy that approximately 40% of AD patients have depressive symptom. The close correlation between cognitive deficits and mental depression suggests a possibility that antidepression treatment might be beneficial to cognitive improvement in AD. The present study, by using tail-suspension test (TST), forced swimming, alternative electro-stimulus Y maze test and immunohistochemistry, examined the neuroprotective effects of desipramine, a newer generation tricyclic antidepressants (TCA), and investigated its possible molecular mechanism. The results showed that: (1) intra-hippocampal injection of A induced depression-like behavior and associative learning deficits in mice, with an increased mean immobility time in tail-suspension and forced swimming test and an increased mean error times in Y maze test; (2) after treatment with desipramine (10mg/kg, i.p.), the average immobility time significantly decreased, from s in A group to s in A plus desipramine group () in TST and from s to s ( or 9, ) in forced swimming test, respectively;the mean error times of mice in Y maze test also significantly decreased, from in A group to in A plus desipramine group (, ); (3) desipramine administration significantly prevented against A-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A. The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice. [ABSTRACT FROM AUTHOR]

This study aimed to examine the relationship between sleep duration and all-cause mortality, and to assess the role of cognitive impairment, physical disability, and chronic conditions on this association among very old adults. A prospective cohort study. Within the Chinese Longitudinal Healthy Longevity Surveys, 17,637 oldest-old aged 80-105 years were followed up to 10 years (2005- 2014). Data on sleep duration at baseline were based on self-report and were categorized as short (<7 hour), moderate (7-9 hours), and long sleep (>9 hours). Information on cognitive function using the Mini-Mental State Examination (MMSE), physical disability using Activities of Daily Living (ADL), and chronic conditions including diabetes, heart disease, stroke, asthma, and cancer were collected at baseline based on a structured questionnaire. Information about vital status was ascertained and confirmed by a close family member or village doctor of the participant during the follow-up. Data were analyzed using Cox proportional hazards models, with adjustment for potential confounders. During the follow-up of 10 years, 11,067 (62.7%) participants died. The multivariate-adjusted hazard ratios (HRs) with 95% confidence interval (CI) for mortality were 1.03 (0.98-1.09) for short sleep and 1.13 (1.08-1.18) for long sleep compared with moderate sleep duration. In stratified analysis by cognitive impairment, physical disability, and chronic conditions, the risk of morality was present only among people with MMSE scores ≤24 but did not differ much when stratified by physical disability and chronic conditions. There was a statistically significant interaction between long sleep and cognitive impairment on mortality (P for interaction =.002). Long sleep duration is associated with higher risk of mortality in very old adults independently of health conditions. Cognitive impairment may enhance this association. These findings suggest that health practitioners and families should be aware of the potential adverse prognosis associated with long sleep. [ABSTRACT FROM AUTHOR]

Studies have suggested that heightened neuroinflammation contributes to the pathogenesis of depressive disorder. A major participant in neuroinflammation is microglia, and fractalkine signaling (which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in healthy brains) has been reported to critically regulate microglial activity. The aim of this study was to investigate whether CX3CR1 deficiency was associated with a different outcome following chronic unpredictable stress (CUS) and the possible mechanism. Wild-type (WT) and CX3CR1-deficient (CX3CR1−/−) mice were subjected to CUS for 3 weeks. CX3CR1−/− mice displayed a better performance through sucrose preference test, open field test and forced swim test, which demonstrated that CX3CR1 deficiency alleviated depressive-like disturbances, such as anhedonia, anxiety or hopelessness. Nevertheless, CX3CR1−/− mice also showed less severe cognitive impairment from the results of Morris Water Maze and Novel object recognition. Long-term potentiation was recorded to test the synaptic plasticity and its result was consistent with that of cognitive ability tests. Both results of real time-PCR and immunofluorescence staining demonstrated that CX3CR1 deficiency facilitated the alternative activation of microglia, thus attenuated the release of inflammatory cytokines, which was verified by ELISA and flow cytometry. Maybe due to the mitigated neuroinflammation, CX3CR1-deficient mice showed higher resilience to CUS-induced blood brain barrier hyperpermeability and loss of dendrite spine (as showed by Golgi and DiI staining) than WT group. All of above results indicated that hampering neuron-microglia communication via CX3CR1-CX3CL1 pathway attenuated the effects of CUS on depressive-like disturbances and cognitive impairment. [ABSTRACT FROM AUTHOR]