Electroacupuncture Improves Cognition in Rats With Sepsis-Associated Encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Although sepsis is effectively managed with the administration of antibiotics and source control, which may include surgical intervention, SAE usually leads to prolonged cognitive dysfunction affecting the quality of life of the patients. In this study, we investigated the possible effect of electroacupuncture (EA) on cognition in a model of SAE induced by cecal ligation and puncture (CLP). MATERIALS AND METHODS: The rats were randomly divided into four groups: the control group, the CLP group, the CLP with EA treatment group (CLP + EA), and the CLP with sham EA treatment group (CLP + sham EA). EA at DU20, LI11, and ST36 or sham EA was performed 30 min daily for 10 consecutive days starting from 2 days before CLP. Then cognitive function was examined by the Morris water maze test. On day 14 after CLP surgery, the synaptic injury, neuron loss, and oxidative stress were studied. RESULTS: Rats with EA treatment showed improved survival rate, spatial learning, and memory abilities. The dendritic spine density, the synaptic proteins, and the hippocampal neuron number were also increased after EA treatment. Furthermore, EA suppressed oxidative stress through regulating the level of malondialdehyde and superoxide dismutase and enhanced the expression of antioxidant nuclear factor erythroid-2-related factor-2 and hemeoxygenase-1. But sham EA did not have the same effect. CONCLUSIONS: EA may protect against SAE-induced cognitive dysfunction by inhibiting synaptic injury, neuronal loss, and oxidative stress, and the nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 signaling pathway may be involved in this effect.

PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease.

Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease-affected brain. Memory impairment in Alzheimer's disease is a manifestation of brain pathologies such as accumulation of amyloid-ß peptide and mitochondrial damage. The underlying pathogenic mechanisms and effective disease-modifying therapies for Alzheimer's disease remain elusive. Here, we demonstrate for the first time that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with Alzheimer's disease pathology. Restoring neuronal PINK1 function strikingly reduces amyloid-ß levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-ß accumulation, mitochondrial abnormalities, impairments in learning and memory, as well as synaptic plasticity at an earlier age than mAPP mice. Notably, gene therapy-mediated PINK1 overexpression promotes the clearance of damaged mitochondria by augmenting autophagy signalling via activation of autophagy receptors (OPTN and NDP52), thereby alleviating amyloid-ß-induced loss of synapses and cognitive decline in Alzheimer's disease mice. Loss of PINK1 activity or blockade of PINK1-mediated signalling (OPTN or NDP52) fails to reverse amyloid-ß-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-ß-mediated mitochondrial and synaptic dysfunctions in a manner requiring activation of autophagy receptor OPTN or NDP52. Thus, activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer's disease.

Particulate matter (PM2.5) exposure season-dependently induces neuronal apoptosis and synaptic injuries.

Epidemiological studies have shown that particulate matter 2.5 (PM2.5) not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM2.5 is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM2.5 exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM2.5 altered the expression of apoptosis-related proteins (mainly bax and bcl-2), activated caspase-3 and caused neuronal apoptosis. Additionally, PM2.5 decreased the levels of synaptic structural protein postsynaptic density (PSD-95) and synaptic functional protein N-methyl-D-aspartate (NMDA) receptor subunit (NR2B) expression. These effects occurred in a season-dependent manner, and PM2.5 collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phosphorylated cAMP-response element binding protein (p-CREB). Based on the findings, we analyzed the correlations between the chemical composition of PM2.5 samples and the biological effects, and confirmed that winter PM2.5 played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.

The cell-permeable Aß1-6A2VTAT(D) peptide reverts synaptopathy induced by Aß1-42wt.

Alzheimer disease (AD) is the most prevalent form of dementia. Loss of hippocampal synapses is the first neurodegenerative event in AD. Synaptic loss has been associated with the accumulation in the brain parenchyma of soluble oligomeric forms of amyloid ß peptide (Aß1-42wt). Clinical observations have shown that a mutation in the APP protein (A673V) causes an early onset AD-type dementia in homozygous carriers while heterozygous carriers are unaffected. This mutation leads to the formation of mutated Aß peptides (Aß1-42A2V) in homozygous patients, while in heterozygous subjects both Aß1-42wt and Aß1-42A2V are present. To better understand the impact of the A673V mutation in AD, we analyzed the synaptotoxic effect of oligomers formed by aggregation of different Aß peptides (Aß1-42wt or Aß1-42A2V) and the combination of the two Aß1-42MIX (Aß1-42wt and Aß1-42A2V) in an in vitro model of synaptic injury. We showed that Aß1-42A2V oligomers are more toxic than Aß1-42wt oligomers in hippocampal neurons, confirming the results previously obtained in cell lines. Furthermore, we reported that oligomers obtained by the combination of both wild type and mutated peptides (Aß1-42MIX) did not exert synaptic toxicity. We concluded that the combination of Aß1-42wt and Aß1-42A2V peptides hinders the toxicity of Aß1-42A2V and counteracts the manifestation of synaptopathy in vitro. Finally we took advantage of this finding to generate a cell-permeable peptide for clinical application, by fusing the first six residues of the Aß1-42A2V to the TAT cargo sequence (Aß1-6A2VTAT(D)). Noteworthy, the treatment with Aß1-6A2VTAT(D) confers neuroprotection against both in vitro and in vivo synaptopathy models. Therefore Aß1-6A2VTAT(D) may represent an innovative therapeutic tool to prevent synaptic degeneration in AD.

Differential effects between one week and four weeks exposure to same mass of SO2 on synaptic plasticity in rat hippocampus.

Sulfur dioxide (SO2 ) is a ubiquitous air pollutant. The previous studies have documented the adverse effects of SO2 on nervous system health, suggesting that acutely SO2 inhalation at high concentration may be associated with neurotoxicity and increase risk of hospitalization and mortality of many brain disorders. However, the remarkable features of air pollution exposure are lifelong duration and at low concentration; and it is rarely reported that whether there are different responses on synapse when rats inhaled same mass of SO2 at low concentration with a longer term. In this study, we evaluated the synaptic plasticity in rat hippocampus after exposure to same mass of SO2 at various concentrations and durations (3.5 and 7 mg/m(3) , 6 h/day, for 4 weeks; and 14 and 28 mg/m(3) , 6 h/day, for 1 week). The results showed that the mRNA level of synaptic plasticity marker Arc, glutamate receptors (GRIA1, GRIA2, GRIN1, GRIN2A, and GRIN2B) and the protein expression of memory related kinase p-CaMKпα were consistently inhibited by SO2 both in 1 week and 4 weeks exposure cases; the protein expression of presynaptic marker synaptophysin, postsynaptic density protein 95 (PSD-95), protein kinase A (PKA), and protein kinase C (PKC) were increased in 1 week exposure case, and decreased in 4 weeks exposure case. Our results indicated that SO2 inhalation caused differential synaptic injury in 1 week and 4 weeks exposure cases, and implied the differential effects might result from different PKA- and/or PKC-mediated signal pathway. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 820-829, 2016.

Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases.

Nitric oxide (NO) is a gasotransmitter that impacts fundamental aspects of neuronal function in large measure through S-nitrosylation, a redox reaction that occurs on regulatory cysteine thiol groups. For instance, S-nitrosylation regulates enzymatic activity of target proteins via inhibition of active site cysteine residues or via allosteric regulation of protein structure. During normal brain function, protein S-nitrosylation serves as an important cellular mechanism that modulates a diverse array of physiological processes, including transcriptional activity, synaptic plasticity, and neuronal survival. In contrast, emerging evidence suggests that aging and disease-linked environmental risk factors exacerbate nitrosative stress via excessive production of NO. Consequently, aberrant S-nitrosylation occurs and represents a common pathological feature that contributes to the onset and progression of multiple neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. In the current review, we highlight recent key findings on aberrant protein S-nitrosylation showing that this reaction triggers protein misfolding, mitochondrial dysfunction, transcriptional dysregulation, synaptic damage, and neuronal injury. Specifically, we discuss the pathological consequences of S-nitrosylated parkin, myocyte enhancer factor 2 (MEF2), dynamin-related protein 1 (Drp1), protein disulfide isomerase (PDI), X-linked inhibitor of apoptosis protein (XIAP), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) under neurodegenerative conditions. We also speculate that intervention to prevent these aberrant S-nitrosylation events may produce novel therapeutic agents to combat neurodegenerative diseases.

Dysregulation of the Gut Microbiota Contributes to Sevoflurane-Induced Cognitive Dysfunction in Aged Mice by Activating the NLRP3 Inflammasome.

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Elevated Ghrelin Promotes Hippocampal Ghrelin Receptor Defects in Humanized Amyloid-ß Knockin Mice During Aging.

BACKGROUND: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer's disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. OBJECTIVE: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAß KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. METHODS: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAß KI mice as well as primary neuron cultures. RESULTS: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. CONCLUSIONS: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.

Telmisartan Alleviates Alzheimer's Disease-Related Neuropathologies and Cognitive Impairments.

BACKGROUND: Alzheimer's disease (AD) is the most common type of neurodegenerative disorder. There are few effective medications for halting the progression of AD. Telmisartan (TEL) is a widely used anti-hypertensive drug approved by FDA. Aside from treating hypertension, TEL has been revealed to provide protection against AD. However, the underlying mechanisms remain unclear. OBJECTIVE: To investigate the mechanisms underlying the beneficial effects of TEL against AD. METHODS: Eight-month-old APP/PS1 mice were administered with 5 mg/kg TEL once per day for 4 successive months. Nesting test, Y-maze test, and Morris water maze test were employed to assess the cognitive and executive functions. Neuronal and synaptic markers, amyloid-ß (Aß) pathology, neuroinflammation, and oxidative stress in the brains were measured. Specifically, components involved in Aß production and degradation pathway were analyzed to explore the mechanisms underlying the therapeutic effect of TEL against Aß pathology. The primary microglia were used to uncover the mechanisms underlying the anti-inflammatory effects of TEL in AD. Additionally, the preventive effect of TEL against AD were investigated using 4-month-old APP/PS1 mice. RESULTS: TEL treatment ameliorated cognitive and executive impairments, neuronal and synaptic injury, Aß pathology, neuroinflammation, and oxidative stress in APP/PS1 mice. The favorable effects of TEL on Aß pathology were achieved by inhibiting enzymatic Aß production and facilitating enzymatic and autophagic Aß degradation. Meanwhile, the anti-inflammatory effects of TEL were accomplished via microglial PPARγ/NLRP3 pathway. The administration of TEL prior to symptom onset prevented AD-related cognitive decline and neuropathologies. CONCLUSION: TEL represents a promising agent for AD prevention and treatment.

Dendrobium nobile Lindl. Alkaloids Ameliorate Aß25-35-Induced Synaptic Deficits by Targeting Wnt/ß-Catenin Pathway in Alzheimer's Disease Models.

BACKGROUND: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AßPP/PS1, and LPS-induced AD animal models, and prevented Aß-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. OBJECTIVE: This study investigated the protective effects of DNLA on synaptic damage in an Aß25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AßPP695, focusing on the Wnt/ß-catenin pathway. METHODS: Sprague-Dawley rats received a single Aß25-35 injection (10µg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aß injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3ß and ß-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AßPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. RESULTS: DNLA ameliorated Aß-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aß-mediated GSK3ß activity and the ß-catenin phosphorylation. In primary neurons and AßPP695-PC12 cells, DNLA restored Aß25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/ß-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aß1-42 and PSD95. CONCLUSION: DNLA rescued Aß-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/ß-catenin signaling pathway to protect synaptic integrity.

Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology.

Synaptic failure underlies cognitive impairment in Alzheimer's disease (AD). Cumulative evidence suggests a strong link between mitochondrial dysfunction and synaptic deficits in AD. We previously found that oligomycin-sensitivity-conferring protein (OSCP) dysfunction produces pronounced neuronal mitochondrial defects in AD brains and a mouse model of AD pathology (5xFAD mice). Here, we prevented OSCP dysfunction by overexpressing OSCP in 5xFAD mouse neurons in vivo (Thy-1 OSCP/5xFAD mice). This approach protected OSCP expression and reduced interaction of amyloid-beta (Aß) with membrane-bound OSCP. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aß-mediated defects in axonal mitochondrial dynamics and motility. Consistent with preserved neuronal mitochondrial function, OSCP overexpression ameliorated synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density, reduced complement-dependent synapse elimination, and improved synaptic transmission, leading to preserved spatial learning and memory. Taken together, our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and implicate OSCP modulation as a potential therapeutic strategy.

Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid ß-Protein-Induced Synapse Loss in Alzheimer's Disease.

Amyloid ß-protein (Aß) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aß causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aß-induced synaptic injury is related to the cleavage of amyloid ß precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aß-induced synaptic injury is markedly reduced in two models of Aß toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aß-induced synaptic damage in the injury pathway mediated by localized caspase activation.

Cerebrospinal Fluid Markers of Synaptic Injury and Functional Connectivity in Alzheimer Disease: Protocol for a Cross-Sectional Study.

BACKGROUND: Synaptic loss is the best surrogate for cognitive decline in Alzheimer disease (AD) and is more closely associated with cognitive function than amyloid or tau pathologies. Neurogranin (Ng) and synaptosome-associated protein-25 (SNAP-25) have demonstrated utility as cerebrospinal fluid (CSF) markers of synaptic injury in presymptomatic and symptomatic AD. While these synaptic markers have been shown to correlate with cognitive impairment and whole brain or regional atrophy in previous studies of AD, to our knowledge, the relationship between fluid markers of synaptic injury and functional brain imaging has not been previously investigated. OBJECTIVE: The main objective of this study is to examine the relationship between CSF markers of synaptic injury (Ng and SNAP-25) and functional connectivity (FC) in the default mode and semantic memory networks in individuals with mild cognitive impairment (MCI) and mild dementia due to AD (Clinical Dementia Rating [CDR] 0.5-1) and cognitively normal controls (CDR 0), adjusting for age, gender, and the apolipoprotein E4 (APOE4) genotype. Secondary objectives include investigating the associations between CSF markers of amyloid and tau pathology (CSF tau, p-tau181, and Aß42) and FC in the default mode and semantic memory networks in AD (CDR 0.5-1) and controls (CDR 0), adjusting for age, gender, and the APOE4 genotype. METHODS: This is a cross-sectional study of individuals with MCI or mild dementia due to AD (CDR 0.5-1; n=20), and cognitively normal controls (CDR 0; n=20). Participants will undergo detailed clinical and neuropsychological assessments, CSF biomarker assessments (CSF Ng, SNAP-25, tau, p-tau181, and Aß42 levels) and functional magnetic resonance imaging assessments, using a Siemens 3.0 Tesla Prisma scanner, during resting state and during the performance of a semantic memory task. All study procedures will be completed within 4 months of enrollment. Partial correlation analyses will examine associations of CSF biomarker measures with FC in the default mode and semantic memory networks in AD and controls. RESULTS: This study was funded by the Chronic Brain Injury Discovery Themes of the Ohio State University College of Medicine. Study enrollment began in April 2018. Study procedures and data analysis are currently underway. Results are expected by December 2019. CONCLUSIONS: Findings from this study will further support the utility of CSF Ng and SNAP-25 as markers of synaptic injury by examining their associations with functional alterations in cortical networks affected by early AD pathology. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14302.

Changes of intestinal flora and the mechanism of NLRP3 inflammasome in elderly mice with cognitive dysfunction induced by sevoflurane anesthesia / 中华行为医学与脑科学杂志

Objective:To investigate changes of intestinal flora and the mechanism of NLRP3 inflammasome in elderly mice with cognitive dysfunction induced by sevoflurane anesthesia.Methods:Eighteen fourteen-month-old male SPF grade C57BL/6J mice were randomly divided into control and sevoflurane groups, with 9 mice in each group. The mice of sevoflurane group inhaled 3% sevoflurane for 2 hours daily for three days. Fecal samples were collected post-exposure 24 hours for 16S rRNA sequencing. Morris water maze was then used to test the cognitive ability. Western blot was used to detect the expressions of synapse-associated proteins, NLRP3 inflammasome-related proteins of hippocampus, and NLRP3 inflammasome-related proteins of colon. Golgi staining was used to observe the number of dendritic spines in the hippocampus. qPCR was used to detect the expression of inflammatory cytokines IL-1β, IL-18, TNF-α mRNA in mice colon and hippocampal tissues.Results:(1) The Morris water maze test showed that the escape latency of the sevoflurane group was longer than the control group, but there was statistical difference only on the fifth day ( P<0.05). In the spatial exploration test, escape latency of the sevoflurane group was higher than that of the control group((49.50±9.99)s, (18.67±7.63)s, t=6.005, P<0.001), and platform crossing frequency was less than that of the control group((0.83±0.75)times, (2.33±1.03)times, t=2.87, P=0.017). (2) Western blot and Golgi staining results showed that the expression of hippocampal synaptic-related proteins and the number of dendritic spines in the sevoflurane group were significantly reduced compared with those in control group (all P<0.05). (3) 16S rRNA sequencing showed significant β-diversity difference between the two groups ( P<0.05). Compared with the control group, potential pathogens that p_Desulfobacterota and g_Desulfovibrio increased significantly in the sevoflurane group (both P<0.05), and beneficial bacteria that p_Verrucomicrobiota and g_Akkermansia decreased significantly (both P<0.05). (4) Compared with the control group, the results of qPCR showed increased expression of inflammatory cytokines TNF-α, IL-1β mRNA in the colon and hippocampal tissues of the sevoflurane group (all P<0.05). Western blot results showed increased expression of NLRP3 inflammasome-related proteins in the colon and hippocampal tissues of the sevoflurane group (both P<0.05). Immunofluorescence results showed the higher fluorescence intensity of ASC in the DG region of the hippocampus of the sevoflurane group compared with the control group ( P<0.01). Conclusion:The cognitive dysfunction model induced by sevoflurane in elderly mice shows neuroinflammatory reactions and synaptic damage, which may be related to intestinal microbiota imbalance and activation of NLRP3 inflammasome.

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-ß, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

The role of myocardin-related transcription factor-A in Aß25-35 induced neuron apoptosis and synapse injury.

Myocardin-related transcription factor-A (MRTF-A) highly expressed in brain has been demonstrated to promote neuronal survival via regulating the transcription of related target genes as a powerful co-activator of serum response factor (SRF). However, the role of MRTF-A in Alzheimer's disease (AD) is still unclear. Here, we showed that MRTF-A was significantly downregulated in cortex of the Aß25-35-induced AD rats, which played a key role in Aß25-35 induced cerebral neuronal degeneration in vitro. Bilateral intracerebroventricular injection of Aß25-35 caused significantly MRTF-A expression decline in cortex of rats, along with significant neuron apoptosis and plasticity damage. In vitro, transfection of MRTF-A into primary cultured cortical neurons prevented Aß25-35 induced neuronal apoptosis and synapses injury. And luciferase reporter assay determined that MRTF-A could bind to and enhance the transactivity of the Mcl-1 (Myeloid cell leukemia-1) and Arc (activity-regulated cytoskeletal-associated protein) promoters by activating the key CArG box element. These data demonstrated that the decreasing of endogenous MRTF-A expression might contribute to the development of AD, whereas the upregulation MRTF-A in neurons could effectively reduce Aß25-35 induced synapse injury and cell apoptosis. And the underlying mechanism might be partially due to MRTF-A-mediated the transcription and expression of Mcl-1 and Arc by triggering the CArG box.

Synergistic exacerbation of mitochondrial and synaptic dysfunction and resultant learning and memory deficit in a mouse model of diabetic Alzheimer's disease.

Diabetes is considered to be a risk factor in Alzheimer's disease (AD) pathogenesis. Although recent evidence indicates that diabetes exaggerates pathologic features of AD, the underlying mechanisms are not well understood. To determine whether mitochondrial perturbation is associated with the contribution of diabetes to AD progression, we characterized mouse models of streptozotocin (STZ)-induced type 1 diabetes and transgenic AD mouse models with diabetes. Brains from mice with STZ-induced diabetes revealed a significant increase of cyclophilin D (CypD) expression, reduced respiratory function, and decreased hippocampal long-term potentiation (LTP); these animals had impaired spatial learning and memory. Hyperglycemia exacerbated the upregulation of CypD, mitochondrial defects, synaptic injury, and cognitive dysfunction in the brains of transgenic AD mice overexpressing amyloid-ß as shown by decreased mitochondrial respiratory complex I and IV enzyme activity and greatly decreased mitochondrial respiratory rate. Concomitantly, hippocampal LTP reduction and spatial learning and memory decline, two early pathologic indicators of AD, were enhanced in the brains of diabetic AD mice. Our results suggest that the synergistic interaction between effects of diabetes and AD on mitochondria may be responsible for brain dysfunction that is in common in both diabetes and AD.

Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.

BACKGROUND: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy. METHODS: We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches. RESULTS: After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal. CONCLUSION: Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.