Metabolomics and Lipidomics Profiling in Asymptomatic Severe Intracranial Arterial Stenosis: Results from a Population-Based Study.

No data are available on the serum metabolomics and lipidomics profiles of people with asymptomatic intracranial arterial stenosis. We explored the characteristic metabolites of individuals with asymptomatic severe intracranial arterial stenosis (asICAS) using untargeted serum metabolomics and lipidomics analyses based on ultra-high-performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). This case-control study included 25 participants with asICAS and 25 age- and sex-matched controls free of asICAS, who were all diagnosed by using magnetic resonance angiography and derived from the same population-based study. Serum metabolomics and lipidomics profiles were determined using UPLC-HRMS, and possible biomarker metabolites were identified. Compared with the control group, the asICAS group showed higher levels of free choline, glycerophosphocholine, uracil, taurine, and four peptide molecules and lower levels of free fatty acids, hydroxydodecanedioic acid, hydroxy valeryl carnitine, hydroxytetradecanedioic acid, and two sphingomyelin molecules. The serum metabolomics and lipidomics profiles for people with asICAS are characterized by abnormal metabolism of sphingomyelin, taurine/hypotaurine, pyrimidine, and protein (peptide). The biological changes in asICAS may mainly involve taurine/hypotaurine, glycerophospholipid, and sphingolipid metabolism pathways. Biofunctional analysis indicated that these differential metabolites were correlated with metabolic diseases such as early myocardial injury, heart failure, and diabetes.

Apolipoprotein E Facilitates Amyloid-ß Oligomer-Induced Tau Phosphorylation.

Hyperphosphorylated tau is one of the key characteristics of Alzheimer's disease (AD), and tau pathology correlates with cognitive impairment in AD better than amyloid-ß (Aß) pathology. Thus, a complete understanding of the relevant factors involved in tau phosphorylation is important for AD treatment. APOEɛ4, the strongest genetic risk factor for AD, was found to be involved in tau pathology in frontotemporal dementia. This result indicated that apolipoprotein E (ApoE) may also participate in tau phosphorylation in AD. In the present study, we injected Aß oligomer (AßO) into the lateral ventricles of wild-type (WT) mice and apoE-/- mice to test the process of tau phosphorylation in the acute phase. We found that the phosphorylated tau and phosphokinase levels were higher in WT mice than in apoE-/- mice. These phenomena were also confirmed in vitro. ApoE ɛ4-treated apoE-/- neurons exhibited more phosphorylated tau than ApoE ɛ2- and ApoE ɛ3-treated neurons. We also found that AßO induced more serious inflammation in WT mice and in ApoE-positive cultured neurons. Anti-inflammatory treatment reduced the phosphorylated tau level induced by AßOs in ApoE-positive neurons. These results suggest that ApoE may facilitate the phosphorylation of tau induced by AßO via inflammation.

Protective effects of tauroursodeoxycholic acid on lipopolysaccharide-induced cognitive impairment and neurotoxicity in mice.

Accumulating evidence has shown that tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of neurological diseases. However, whether TGR5 agonist TUDCA can improve lipopolysaccharide (LPS)-induced cognitive impairment in mice is less clear. Using a model of cognitive impairment with LPS (2.0 µg) we investigated the effects of TUDCA (200 or 400 µg) on cognitive dysfunction and neurotoxicity in mice. Both Morris water maze and Y-maze avoidance tests showed that TUDCA treatment significantly alleviated LPS-induced behavioral impairments. More importantly, we found that TUDCA treatment reversed TGR5 down-regulation, prevented neuroinflammation via inhibiting NF-κB signaling in the hippocampus of LPS-treated mice. Additionally, TUDCA treatment decreased LPS-induced apoptosis through decreasing TUNEL-positive cells and the overexpression of caspase-3, increasing the ratio of Bcl-2/Bax. TUDCA treatment also ameliorated synaptic plasticity impairments by increasing the ratio of mBDNF/proBDNF, the number of dendritic spines and the expression of synapse-associated proteins in the hippocampus. Our results indicated that TUDCA can improve cognitive impairment and neurotoxicity induced by LPS in mice, which is involved in TGR5-mediated NF-κB signaling.

Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.

Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease (AD) and memory impairment. Herein, we evaluated the neuroprotective effects of 6-ethyl-23(S)-methyl-cholic acid (INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the LPS-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of LPS remarkably induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests, which were ameliorated by INT-777 (1.5 or 3.0 µg/mouse, i.c.v.) treatment. Importantly, INT-777 treatment reversed LPS-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, evidenced by lower proinflammatory cytokines, less activation of microglia, and increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus and frontal cortex. In addition, INT-777 treatment also suppressed neuronal apoptosis, as indicated by the reduction of TUNEL-positive cells, decreased activation of caspase-3, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction as evidenced by the upregulation of PSD95 and synaptophysin in the hippocampus and frontal cortex. Taken together, this study showed the potential neuroprotective effects of INT-777 against LPS-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.

Neuroprotective effect of recombinant adeno-associated virus human thioredoxin-PR39 on acute cerebral infarction in rats.

The recombinant adeno-associated virus human thioredoxin-PR39 (rAAV/hTRX-PR39) has been demonstrated to have a protective effect on hypoxic cells. The present study aimed to explore the potential effect of rAAV/hTRX-PR39 on acute cerebral infarction in rats. Middle cerebral artery occlusion (MCAO) model rats were produced and divided into three groups: Normal saline group, empty virus group (rAAV, without hTRX-PR39 cDNA) and rAAV/hTRX-PR39 group. Hematoxylin and eosin staining and electron microscopy observation were used to assess the morphological changes of ischemic brain tissue during different periods. Immunohistochemistry was employed to detect the expression of CD34 to reflect angiogenesis of ischemic brain tissue. Rats treated with rAAV/hTRX-PR39 showed an alleviated degree of ischemic brain edema relative to that in control groups, suggesting PR39 can ameliorate brain damage after cerebral ischemia. In the rAAV/hTRX-PR39 group, CD34-positive cells were significantly increased in ischemic brain tissues compared to control groups. Furthermore, CD34-positive cells were primarily observed around the perivascular in ischemic brain, indicating the angiogenesis role of PR39 in ischemic brain. The present findings suggest that PR39 could effectively ameliorate ischemic brain damage and promote angiogenesis, which may contribute to the treatment of acute cerebral infarction.

Neuroprotective effects of INT-777 against Aß1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.

Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aß) deposition plays a causative role in Alzheimer's disease (AD). Herein, we evaluated the neuroprotective effects of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the Aß1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aß1-42 (410 pmol/mouse; 5 µl) into the mouse brain induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction. In contrast, INT-777 (1.5 or 3.0 µg/mouse, i.c.v.) significantly improved Aß1-42-induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aß1-42-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells, decreased caspase-3 activation, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic and presynaptic proteins (PSD95 and synaptophysin) in Aß1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aß1-42-induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD.

Antidepressant-like effect of zileuton is accompanied by hippocampal neuroinflammation reduction and CREB/BDNF upregulation in lipopolysaccharide-challenged mice.

BACKGROUND: Recent studies demonstrated beneficial effects of zileuton, a 5-lipoxygenase (5LO) inhibitor, on some brain diseases in animal models, but the role of zileuton in the depression remains unknown. METHODS: We investigated the effects of zileuton on depressive behaviors using tail suspension test (TST), forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice injected with lipopolysaccharide (LPS). The 5LO level, activation of microglia, NF-κB p65, TNF-α, IL-1ß, brain-derived neurotrophic factor (BDNF), and c-AMP response element-binding protein (CREB) were determined in the mouse hippocampus. RESULTS: We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and was reversed by fluoxetine administration. Zileuton significantly suppressed LPS-induced depressive behaviors, evidenced by the decreases in immobility time in TST and FST, as well as the latency to feed in NSFT. This treatment pronouncedly alleviated LPS-induced neuroinflammatory response, characterized by decreased 5LO, suppressed activation of microglia, decreased NF-κB p65, TNF-α and IL-1ß, and significantly increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus of the LPS-challenged mice. CONCLUSIONS: Zileuton abrogates LPS-induced depressive-like behaviors and neuroinflammation, and enhances CREB/BDNF signaling in the hippocampus, suggesting that zileuton could have potential therapeutic value for depression.

Targeted inhibition of RAGE reduces amyloid-ß influx across the blood-brain barrier and improves cognitive deficits in db/db mice.

AIMS: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid ß (Aß) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. METHODS: Aß influx across the BBB was determined by intra-arterial infusion of 125I-Aß1-40. Receptor for advanced glycation end products (RAGE), Aß, NF-κB p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. RESULTS: FPS-ZM1 (1.0 mg/kg i.p.) inhibited Aß influx across the BBB and expression of RAGE participating in Aß influx, consequently decreased hippocampal Aß1-40 and Aß1-42 in db/db mice. After FPS-ZM1 treatment, NF-κB signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS-ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. CONCLUSION: Downregulation of abnormal Aß influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.

Neuropeptides Exert Neuroprotective Effects in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits and neuronal loss. Deposition of beta-amyloid peptide (Aß) causes neurotoxicity through the formation of plaques in brains of Alzheimer's disease. Numerous studies have indicated that the neuropeptides including ghrelin, neurotensin, pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y, substance P and orexin are closely related to the pathophysiology of Alzheimer's disease. The levels of neuropeptides and their receptors change in Alzheimer's disease. These neuropeptides exert neuroprotective roles mainly through preventing Aß accumulation, increasing neuronal glucose transport, increasing the production of neurotrophins, inhibiting endoplasmic reticulum stress and autophagy, modulating potassium channel activity and hippocampal long-term potentiation. Therefore, the neuropeptides may function as potential drug targets in the prevention and cure of Alzheimer's disease.

Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases.

PURPOSE: Stroke is a major public health concern with high rates of morbidity and mortality worldwide. Cerebral ischemia and infarction are commonly associated with stroke. Currently used medications, though effective, are also associated with adverse effects. Development of effective neuroprotective agents with fewer side effects would be of clinical value. We evaluated the effects of Withaferin A (WA), a steroidal lactone derived from the plant Withania somnifera, on experimentally induced cerebral infarction. MATERIALS AND METHODS: The ability of WA to inhibit neuroapoptosis and modulate vascular smooth muscle cell (VSMC) migration and PI3K/Akt signaling was assessed. Separate groups of Sprague Dawley rats were subjected to cerebral occlusion and reperfused for 24h. RESULTS: WA treatment (25, 50 or 100mg/kg bodyweight) significantly reduced the infarct area in a carotid ligation model; WA reduced intimal hyperplasia and proliferating cell nuclear antigen (PCNA)-positive cell counts. Western blotting analysis revealed significantly suppressed PI3K/Akt signaling following cerebral ischemia/reperfusion injury. WA supplementation was found to downregulate apoptotic pathway proteins. WA suppressed PTEN and enhanced p-Akt and GSK-3ß levels and elevated mTORc1, cyclinD1 and NF-κB p65 expression, suggesting activation of the PI3K/Akt pathway. In vitro studies with PDGF-stimulated A7r5 cells revealed that WA exposure severely downregulated matrix metalloproteinases (MMP)-2 and -9 and inhibited migration of A7r5 cells. Additionally, WA reduced the proliferation of A7r5 cells significantly. CONCLUSIONS: WA exerted neuroprotective effects by activating the PI3K/Akt pathway, modulating the expression of MMPs, and inhibiting the migration of VSMCs.

Orexin-A increases the firing activity of hippocampal CA1 neurons through orexin-1 receptors.

Orexins including two peptides, orexin-A and orexin-B, are produced in the posterior lateral hypothalamus. Much evidence has indicated that central orexinergic systems play numerous functions including energy metabolism, feeding behavior, sleep/wakefulness, and neuroendocrine and sympathetic activation. Morphological studies have shown that the hippocampal CA1 regions receive orexinergic innervation originating from the hypothalamus. Positive orexin-1 (OX1 ) receptors are detected in the CA1 regions. Previous behavioral studies have shown that microinjection of OX1 receptor antagonist into the hippocampus impairs acquisition and consolidation of spatial memory. However, up to now, little has been known about the direct electrophysiological effects of orexin-A on hippocampal CA1 neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micropressure administration of orexin-A significantly increased the spontaneous firing rate from 2.96 ± 0.85 to 8.45 ± 1.86 Hz (P < 0.001) in 15 out of the 23 hippocampal CA1 neurons in male rats. Furthermore, application of the specific OX1 receptor antagonist SB-334867 alone significantly decreased the firing rate from 4.02 ± 1.08 to 2.11 ± 0.58 Hz in 7 out of the 17 neurons (P < 0.05), suggesting that endogenous orexinergic systems modulate the firing activity of CA1 neurons. Coapplication of SB-334867 completely blocked orexin-A-induced excitation of hippocampal CA1 neurons. The PLC pathway may be involved in activation of OX1 receptor-induced excitation of CA1 neurons. Taken together, the present study's results suggest that orexin-A produces excitatory effects on hippocampal neurons via OX1 receptors. © 2016 Wiley Periodicals, Inc.

Effects of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper limb motor dysfunction in patients with subacute cerebral infarction.

Studies have confirmed that low-frequency repetitive transcranial magnetic stimulation can decrease the activity of cortical neurons, and high-frequency repetitive transcranial magnetic stimulation can increase the excitability of cortical neurons. However, there are few studies concerning the use of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper-limb motor function after cerebral infarction. We hypothesized that different frequencies of repetitive transcranial magnetic stimulation in patients with cerebral infarction would produce different effects on the recovery of upper-limb motor function. This study enrolled 127 patients with upper-limb dysfunction during the subacute phase of cerebral infarction. These patients were randomly assigned to three groups. The low-frequency group comprised 42 patients who were treated with 1 Hz repetitive transcranial magnetic stimulation on the contralateral hemisphere primary motor cortex (M1). The high-frequency group comprised 43 patients who were treated with 10 Hz repetitive transcranial magnetic stimulation on ipsilateral M1. Finally, the sham group comprised 42 patients who were treated with 10 Hz of false stimulation on ipsilateral M1. A total of 135 seconds of stimulation was applied in the sham group and high-frequency group. At 2 weeks after treatment, cortical latency of motor-evoked potentials and central motor conduction time were significantly lower compared with before treatment. Moreover, motor function scores were significantly improved. The above indices for the low- and high-frequency groups were significantly different compared with the sham group. However, there was no significant difference between the low- and high-frequency groups. The results show that low- and high-frequency repetitive transcranial magnetic stimulation can similarly improve upper-limb motor function in patients with cerebral infarction.

The relationship between high-sensitivity C-reactive protein at admission and post stroke depression: a 6-month follow-up study.

OBJECTIVE: A large body of evidence suggests that stroke and depression are accompanied by activation of inflammatory pathways. Thus, the primary purpose of this study was to assess the high-sensitivity C-reactive protein (Hs-CRP) to the presence of post stroke depression (PSD). METHODS: Two hundred and twenty-six ischemic stroke patients admitted to the hospital within the first 24 hours after stroke onset were consecutively recruited and followed up for 6 months. Clinical information was collected. Serum Hs-CRP levels were measured at baseline. Based on the symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for depression at 6-month after stroke. RESULTS: At 6-month, ninety-five patients (42.0%) showed depression at 6 months after admission and in 69 patients (30.5%) this depression was classified as major. In the 69 patients with major depression, our results showed significantly higher Hs-CRP levels (1.54[IQR, 0.79-2.27]mg/dL vs. 0.43[IQR, 0.31-1.27]mg/dL, P<0.0001) at admission than patients without major depression. After adjusting for NIHSS on admission and all other recorded confounders, Hs-CRP still was an independent predicator of PSD with an adjusted OR of 1.339 (95% CI, 1.231-1.456; P<0.001). Further, in our study, we found that an increased risk of PSD was associated with serum Hs-CRP levels ≥0.85mg/dL (adjusted OR 7.830, 95% CI: 4.193-14.620) after adjusting for above recorded confounders. CONCLUSION: Elevated Hs-CRP serum levels at admission was found to be associated with depression 6-month after stroke, suggesting that these alterations might participate in the pathophysiology of depression symptoms in stroke patients.

Potential role of recombinant adeno-associated virus human thioredoxin-PR39 in cell and vascular protection against hypoxia.

The aim of the present study was to successfully construct a recombinant adeno-associated virus (rAAV) vector containing the human thioredoxin (hTRX)-PR39 chimeric gene (rAAV/hTRX-PR39), and verify that the vector was able to maintain a sustained, stable and efficient expression to achieve protein production in the cell. In the present study, a chicken embryo model was utilized to analyze the therapeutical effect of rAAV/hTRX-PR39 in cerebral ischemia diseases. ECV304 cells were transfected with rAAV/hTRX-PR39 and incubated under conditions of 20, 5 and 1% O2. Subsequently, the expression levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, fibroblast growth factor receptor (FGFR)-1 and syndecan-4 were detected by reverse transcription-quantitative polymerase chain reaction. Under hypoxic conditions, the mRNA expression levels of VEGF, VEGFR-1, VEGFR-2, FGFR-1 and syndecan-4 were found to increase in the PR39-transfected group when compared with the control group, while no statistically significant difference was observed between the PR39-transfected group and the control group under conditions of 20% O2. In addition, hTRX-PR39 was shown to increase the density of the vasculature and the survival rate of the chick embryos. Under hypoxic conditions, it was hypothesized that rAAV/hTRX-PR39 was capable of promoting angiogenesis, which may subsequently protect the cells from impairment by hypoxia. In conclusion, rAAV/hTRX-PR39 was demonstrated to promote vascularization and cell survival in hypoxia; thus, rAAV/hTRX-PR39 may have potential for use in therapy targeting cerebral ischemia.

Effect of Carotid Artery Stenting on Cognitive Function in Patients with Internal Carotid Artery Stenosis and Cerebral Lacunar Infarction: A 3-Year Follow-Up Study in China.

BACKGROUND AND OBJECTIVES: Carotid artery stenting (CAS) is an important therapeutic strategy for patients with carotid artery stenosis. However, the potential influence of CAS on cognitive function in patients with carotid artery stenosis and cerebral lacunar infarction has not been determined. This study investigated changes in cognitive function associated with CAS and the factors related to these changes. METHODS: This prospective cohort study comprised 579 Chinese patients with cerebral lacunar infarction and carotid artery stenosis for whom CAS was indicated, and a matched control group of 552 healthy individuals. Cognitive function before CAS and at scheduled intervals from 6 months to 3 years was assessed with instruments that included the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scale. Potential factors that might affect cognitive function were analyzed via logistic regression. RESULTS: The MMSE and MoCA scores of the patients before CAS were significantly lower than that of the control subjects. These scores were significantly higher 6 months after CAS and sustained or increased throughout the 3-year follow-up. Also significantly improved after CAS from baseline were scores for an alternating trail test, cube copying, clock-drawing, attention, and delayed recall in an auditory-verbal learning test. Logistic regression analyses showed that age greater than 65 y, little education, diabetes, and hypertension were independent risk factors for deteriorated MoCA scores 3 years after CAS. CONCLUSION: CAS was associated with significantly improved cognitive function in cerebral lacunar infarction patients with severe stenosis.

Expression of Tau protein in rats with cognitive dysfunction induced by cerebral hypoperfusion.

The aim of this study was to investigate the relationship between chronic cerebral hypoperfusion and the occurrence and development of Alzheimer's disease (AD). A cerebral hypoperfusion rat model was established by two vessels occlusion (2VO). The cognitive function of the rats with chronic cerebral hypoperfusion and the expression of p-Tau protein in the hippocampus were observed dynamically. Before the operation, no differences were observed in the cognitive functions of the control and 2VO group (P > 0.05). However, a significant difference was found at 2, 4, 8, and 12 weeks after the operation. The shock number required to reach the "learned" standard in the 2VO group increased remarkably compared with that of the control group (P < 0.01). With the passage of time, the shock number in the model group increased gradually. The p-Tau-positive cells in the CA1 region of the hippocampus also increased markedly in the model group in a time-dependent manner as compared with that in the control group (P < 0.01). Cerebral hypoperfusion can cause and aggravate the phosphorylation of Tau protein in the brain, leading to cognitive dysfunction. Therefore, this protein is an important initiating and promoting factor involved in the development of AD.

Effects of APP 5-mer peptide analogue P165 on the synaptic proteins and insulin signal transduction proteins.

Diabetic encephalopathy (DE) is one of risk factors for Alzheimer's disease (AD). Our previous findings indicated that DE animals had impairment of learning and memory and degeneration of hippocampal neurons, which could be improved by neurotrophic peptide. APP 17-mer peptide is a synthesized peptide sequenced from soluble amyloid precursor protein. APP 17-mer peptide has neural protective effect, but is susceptible to enzyme degradation. Soluble APP 5-mer peptide is the active form of APP 17-mer peptide, and composed of arginine, glutamic acid, arginine, methionine and serine. P165, an APP 5-mer peptide analog reconstructed by our lab, is resistant to enzyme degradation, and can be orally used to protect neurons. In the present study, high glucose and Aß25-35 were used to cause injury to human neuroblastoma cell line SH-SY5Y in vitro, and streptozotocin was used to induce diabetes in mice in vivo. The changes in synaptic proteins and proteins of insulin signal transduction which closely correlate with learning and memory were detected in these cells and the brain of mice. Results showed that P165 could up-regulate the expression of α-synuclein and insulin receptor (IR), down-regulate the expression of insulin receptor substrate-1 (IRS-1), PSD-95, Shank1 and MAPK expression. All these findings suggest that nicorandil might be a potential drug used for the treatment of AD.

Postural sway in idiopathic rapid eye movement sleep behavior disorder: a potential marker of prodromal Parkinson's disease.

There is compelling evidence that postural instability occurs at very early clinical stages of Parkinson's disease (PD), making it tempting to speculate that changes in postural sway may even occur at a prodromal phase. Studies estimate that approximately half of patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) will eventually develop PD, so RBD may be an indicator of prodromal PD. This study was undertaken to investigate postural sway and its relation to stereopsis function in patients with RBD. We examined 24 patients with polysomnography-confirmed RBD and 23 healthy, sex-and age-matched control subjects. Postural sway was measured with an accelerometer at the center of mass at the lower spine. Subjects were asked to stand quietly for 30s under two usual conditions (eyes open and eyes closed) and three challenging conditions (eyes open with dual task, eyes closed with dual task, and tandem standing). Stereopsis was assessed using the Titmus fly test. RBD patients showed an increased variability of trunk acceleration and a decrease of smoothness of sway, compared to control subjects. These differences reached significance in the challenging conditions. RBD patients demonstrated significant impairment in stereopsis. There were statistically significant correlations between log seconds of arc of the Titmus test and some sway parameters within the RBD group. RBD patients with abnormal stereopsis showed a significant increase of JERK values compared to patients with normal stereopsis in the challenging conditions. Our results indicate that idiopathic RBD patients, especially with abnormal stereopsis, have subtle signs of postural instability under challenging conditions. Postural sway performance may serve as a biological marker for prodromal PD.

Soluble oligomers and fibrillar species of amyloid ß-peptide differentially affect cognitive functions and hippocampal inflammatory response.

Two major active species of ß-amyloid protein (Aß), fibrillar Aß1-42 (FAß) and soluble Aß1-42 oligomers (AßO), are known to play important roles in the pathogenesis of Alzheimer's disease. However, the differences between them are largely unknown. In this study, we explored the effects of FAß and AßO on cognitive functions and hippocampal inflammatory response through a 30-days infusion of FAß or AßO (144pmol/d) into the left lateral ventricles of the rat brain. Morris water maze showed that the impairment of learning and memory functions was much more significant in the AßO-infused rats, compared to the FAß-infused rats. AßO-induced neurodegeneration and ultrastructure damage in CA1 neurons were more remarkable than those induced by FAß. Compared to FAß, AßO exerted more potent effects on the expressions of inflammatory factors toll-like receptor 4 and TNF-α and activation of NF-κB signaling. Taken together, our results from in vivo model demonstrate that AßO is more neurotoxic than FAß, and this neurotoxicity may be related to NF-κB-medicated inflammatory response.

Effects of fibrillar Aß(1-40) on the viability of primary cultures of cholinergic neurons and the expression of insulin signaling-related proteins.

To investigate the effects of fibrillar Aß(1-40) on the morphology and viability of cholinergic neurons and the involvement of the insulin-signaling pathway, we established primary cultures of rat basal forebrain cholinergic neurons and observed their responses to treatment with fibrillar Aß(1-40) at different concentrations for different durations. Cell morphology was examined under microscope after immunofluorescence staining for neurofilament protein, cell vitality accessed by the Methyl thiazolyl tetrazolium assay, and expressions of a panel of insulin signaling-related proteins was detected by Western blot analysis. We show here that, at low concentrations of 0.1-1.0 micromol/L, fibrillar Aß(1-40) had little effects on the cells; however, at higher concentrations of 2-10 µmicromol/L, it caused pathological changes, decreased the cell viability, and reduced the expression of insulin receptor, insulin receptor substrate-I, Protein Kinase B, and B cell lymphoma/leukemia-2 in a dose- and time-dependent manner. These results demonstrate that fibrillar Aß(1-40) not only decreases the viability of cholinergic neuron but also down regulates the expression of important proteins in the insulin signal transduction pathway. We speculate that fibrillar Aß(1-40) may contribute to the pathogenesis of Alzheimer's through disrupting the insulin signaling pathway, therefore decreasing neuronal activity and eventually leading to the apoptosis and cell loss.