The association between plasma trans-fatty acids level and migraine: A cross-sectional study from NHANES 1999-2000.

OBJECTIVES: Trans-fatty acid (TFA) has been linked to an increased risk of a variety of diseases, such as cardiovascular disease (CVD), diabetes, and cancer. However, the relationship between plasma TFAs and migraine is little known. The current study aimed to determine the association between plasma TFAs and migraine in a large cross-sectional study among U.S. adults. METHODS: The participants from the US National Health and Nutrition Examination Survey (NHANES) were included during the period 1999-2000. The plasma concentrations of four major TFAs, including palmitelaidic acid (C16:1n-7t), elaidic acid (C18:1n-9t), vaccenic acid (C18:1n-7t), and linolelaidic acid (C18:2n-6t, 9t) were measured by gas chromatography/mass spectrometry (GC/MS). The presence of migraine headache was determined by self-report questionnaire. Weighted multivariable logistic regressions and restricted cubic spline (RCS) regressions were explored to assess the relationship between plasma TFAs and migraine. Furthermore, stratified analysis and testing of interaction terms were used to evaluate the effect modification by sex, age, race/ethnicity, family income, and BMI. RESULTS: A total of 1534 participants were included. The overall weighted prevalence of severe headache or migraine was 21.2 %. After adjusting for all potential covariates, plasma levels of elaidic acid and linolelaidic acid were positively associated with migraine. The adjusted OR values were 1.18 (95 %CI: 1.08-1.29, p=0.014, per 10 units increase) and 1.24 (95 %CI: 1.07-1.44, p=0.024). Then the included participants were divided into 2-quantiles by plasma TFA levels. Compared with participants with lower plasma levels of elaidic acid and linolelaidic acid (Q1 groups), those in the Q2 group had a higher prevalence of migraine when adjusted for all covariates in Model 2. The adjusted OR values were 2.43 (95 %CI: 1.14-5.18, p=0.037) for elaidic acid, and 2.18 (95 %CI: 1.14-4.20, p=0.036) for linolelaidic acid. Results were robust when analyses were stratified by sex, age, race/ethnicity, family income, and BMI, and no effect modification on the association was found. CONCLUSIONS: Our results demonstrated a positive association between migraine prevalence and plasma levels of elaidic acid and linolelaidic acid in US adults. These results highlight the connection between circulating TFAs and migraine.

A case report of Andersen-Tawil syndrome misdiagnosed with myodystrophy.

Andersen-Tawil syndrome (ATS) is a rare periodic paralysis caused by the KCNJ2 gene mutation. Here, we report on an ATS patient misdiagnosed with myodystrophy. A 66-year-old man presented with a 60-year history of episodic weakness in the proximal muscles of the upper and lower limbs. The man has been diagnosed with muscle pathology and has undergone genetic examinations in many hospitals since childhood. We conducted a correct diagnosis in combination with the patient's history, electrical physiology, and genetic analysis and identified a heterozygous KCNJ2 gene variant (c.220A > G; p.T74A). Patients with ATS can develop permanent myasthenia characterized by chronic progressive myopathy. ATS patients should also pay special attention to the risks of anesthesia in surgery, including malignant hyperthermia (MH), muscle spasms affecting tracheal intubation or ventilation, and ventilator weakness. Early diagnosis and therapy could help delay the onset of myasthenia and prevent risks associated with anesthesia accidents.

DHCR24 reverses Alzheimer's disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice.

Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer's disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-ß deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD.

Cellular cholesterol loss by DHCR24 knockdown leads to Aß production by changing APP intracellular localization.

For the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-ß (Aß) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aß generation. As a highly controversial issue in Alzheimer's disease pathogenesis, the apparent contradiction prompted us to again explore the role of cellular cholesterol in Aß production. Here, we adopted new neuronal and astrocytic cell models induced by 3ß-hydroxysterol-Δ24 reductase (DHCR24), which obviously differ from the widely used cell models with overexpressing amyloid precursor protein (APP) in the majority of previous studies. In neuronal and astrocytic cell model, we found that deficiency of cellular cholesterol by DHCR24 knockdown obviously increased intracellular and extracellular Aß generation. Importantly, in cell models with overexpressing APP, we found that APP overexpression could disrupt cellular cholesterol homeostasis and affect function of cells, coupled with the increase of APP ß-cleavage product, 99-residue transmembrane C-terminal domain. Therefore, we suppose the results derived from the APP knockin models will need to be re-evaluated. One rational explanation for the discrepancy between our outcomes and the previous studies could be attributed to the two different cell models. Mechanistically, we showed that cellular cholesterol loss obviously altered APP intracellular localization by affecting cholesterol-related trafficking protein of APP. Therefore, our outcomes strongly support cellular cholesterol loss by DHCR24 knockdown leads to Aß production.

Isolated transient vertigo due to TIA: challenge for diagnosis and therapy.

As a prevalent vertigo disease in the clinic, isolated transient vertigo can present as a vertigo episode without focal signs and always free of symptoms on presentation. Previous studies showed a part of isolated transient vertigo events had a high risk of stroke during follow-up. However, how to discern posterior circulation ischemia become a great challenge for clinicians, especially in emergency, neurology, and ENT departments. Routine besides, hematological, and imaging examinations are often difficult provide a clear etiological diagnosis. Hence, this article reviews current knowledge about the epidemiology, risk factors, offending lesions, and clinical manifestation of transient ischemic attack (TIA) presenting as isolated transient vertigo. In addition, we summarize several advances in besides examinations, serum biomarkers, and imaging technologies to better identify stroke events. Finally, the current situation of therapy was briefly retrospected. Here we present a critical clinical puzzle that needs to be solved in the future. Of note, there is a still lack of high-quality studies in this field. The article reviews the keys to the diagnosis of isolated transient vertigo due to TIA and provides us with more methods to screen for high-risk stroke populations.

Clinical efficacy and safety of low-dose doxepin in Chinese patients with generalized anxiety disorder: A before-after study.

Clinical and animal studies have reported that low-dose doxepin may have positive effects on generalized anxiety disorder (GAD); however, its effectiveness and clinical safety are less well understood. This study is a before-after study and aims to investigate the effectiveness and side effects of low-dose doxepin by evaluating Hamilton Anxiety Scale (HAMA) scores, hormones, blood glucose, serum lipids, body weight, and body mass index (BMI) in patients with GAD. Forty-nine patients (20 males and 29 females) with GAD were randomly assigned to receive low-dose doxepin (6.25 mg-12.5 mg per day) for 12 weeks between February 2015 and March 2016. HAMA scores, fasting blood glucose (FBG) body weight, BMI, and some serum biochemical indexes, such as adrenocorticotropic hormone (ACTH), free triiodothyronine (FT3), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC), and FBG, were assessed during pretreatment and post-treatment. Mean scores of HAMA decreased from 19.50 ±â€…1.22 to 8.50 ±â€…3.61 after low-dose doxepin treatment (P < .01). The serum levels of ACTH (4.33 ±â€…2.14 vs 6.12 ±â€…3.02 pmol/L), FT3 (4.78 ±â€…0.51 vs 5.15 ±â€…0.52 pg/mL), TC (4.55 ±â€…1.01 vs 5.93 ±â€…1.66 mmol/L), TG (1.69 ±â€…1.51 vs 3.39 ±â€…2.86 mmol/L), and LDLC (2.43 ±â€…0.88 vs 3.76 ±â€…1.25 mmol/L), and FBG (5.06 ±â€…0.43 vs 5.78 ±â€…0.81 mmol/L) were higher than that pretreatment with a significant difference (P < .01). Bodyweight (62.00 ±â€…7.45 vs 64.00 ±â€…6.44 kg, P = .23) and BMI (23.70 ±â€…2.35 vs 24.48 ±â€…2.11 kg/m2, P = .14) had no difference after treatment. These results suggest that low-dose doxepin has beneficial clinical efficacy and safety. Low-dose doxepin can ameliorate anxiety in GAD patients and has some effects on neuroendocrine systems and the metabolic activity of serum glucose and lipid.

DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent Ras/MEK/ERK Signaling Pathway in C8D1A Astrocytes.

The synthetase 3ß-hydroxysterol-Δ24 reductase (DHCR24) is a key regulator involved in cholesterol synthesis and homeostasis. A growing body of evidence indicates that DHCR24 is downregulated in the brain of various models of Alzheimer's disease (AD), such as astrocytes isolated from AD mice. For the past decades, astrocytic tau pathology has been found in AD patients, while the origin of phosphorylated tau in astrocytes remains unknown. A previous study suggests that downregulation of DHCR24 is associated with neuronal tau hyperphosphorylation. Herein, the present study is to explore whether DHCR24 deficiency can also affect tau phosphorylation in astrocytes. Here, we showed that DHCR24 knockdown could induce tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, and Ser396 sites in C8D1A astrocytes. Meanwhile, we found that DHCR24-silencing cells had reduced the level of free cholesterol in the plasma membrane and intracellular organelles, as well as cholesterol esters. Furthermore, reduced cellular cholesterol level caused a decreased level of the caveolae-associated protein, cavin1, which disrupted lipid rafts/caveolae and activated rafts/caveolae-dependent Ras/MEK/ERK signaling pathway. In contrast, overexpression of DHCR24 prevented the overactivation of Ras/MEK/ERK signaling by increasing cellular cholesterol content, therefore decreasing tau hyperphosphorylation in C8D1A astrocytes. Herein, we firstly found that DHCR24 knockdown can lead to tau hyperphosphorylation in the astrocyte itself by activating lipid raft-dependent Ras/MEK/ERK signaling, which might contribute to the pathogenesis of AD and other degenerative tauopathies.

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis.

Previous studies show that 3ß-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in ß-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.

DHCR24 Knock-Down Induced Tau Hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 Epitopes and Inhibition of Autophagy by Overactivation of GSK3ß/mTOR Signaling.

Accumulating evidences supported that knock-down of DHCR24 is linked to the pathological risk factors of AD, suggesting a potential role of DHCR24 in AD pathogenesis. However, the molecular mechanism link between DHCR24 and tauopathy remains unknown. Here, in order to elucidate the relationship between DHCR24 and tauopathy, we will focus on the effect of DHCR24 on the tau hyperphosphorylation at some toxic sites. In present study, we found that DHCR24 knock-down significantly lead to the hyperphosphorylation of tau sites at Thr181, Ser199, Thr231, Ser262, Ser396. Moreover, DHCR24 knock-down also increase the accumulation of p62 protein, simultaneously decreased the ratio of LC3-II/LC3-I and the number of autophagosome compared to the control groups, suggesting the inhibition of autophagy activity. In contrast, DHCR24 knock-in obviously abolished the effect of DHCR24 knock-down on tau hyperphosphrylation and autophagy. In addition, to elucidate the association between DHCR24 and tauopathy, we further showed that the level of plasma membrane cholesterol, lipid raft-anchored protein caveolin-1, and concomitantly total I class PI3-K (p110α), phospho-Akt (Thr308 and Ser473) were significantly decreased, resulting in the disruption of lipid raft/caveola and inhibition of PI3-K/Akt signaling in silencing DHCR24 SH-SY5Y cells compared to control groups. At the same time, DHCR24 knock-down simultaneously decreased the level of phosphorylated GSK3ß at Ser9 (inactive form) and increased the level of phosphorylated mTOR at Ser2448 (active form), leading to overactivation of GSK3ß and mTOR signaling. On the contrary, DHCR24 knock-in largely increased the level of membrane cholesterol and caveolin-1, suggesting the enhancement of lipid raft/caveola. And synchronously DHCR24 knock-in also abolished the effect of DHCR24 knock-down on the inhibition of PI3-K/Akt signaling as well as the overactivation of GSK3ß and mTOR signaling. Collectively, our data strongly supported DHCR24 knock-down lead to tau hyperphosphorylation and the inhibition of autophagy by a lipid raft-dependent PI3-K/Akt-mediated GSK3ß and mTOR signaling. Taking together, our results firstly demonstrated that the decrease of plasma membrane cholesterol mediated by DHCR24 deficiency might contribute to the tauopathy in AD and other tauopathies.

DHCR24 Knockdown Lead to Hyperphosphorylation of Tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites by Membrane Lipid-Raft Dependent PP2A Signaling in SH-SY5Y Cells.

Accumulating data suggest that the downregulation of DHCR24 is linked to the pathological risk factors of AD, denoting a potential role of DHCR24 in AD pathogenesis. However, it remains unclear whether the downregulation of DHCR24 affects the abnormal heper-phosphorylation of tau protein, which is involved in tauopathy. In present papers, immunofluorescence and Filipin III fluorescence results showed that DHCR24 knockdown significantly lowered the level of plasma membrane cholesterol and expression level of membrane lipid-raft structural protein caveolin-1; and overexpression of DHCR24 could increase the plasma membrane cholesterol levels and facilitating caveolae structure through increase the expression of caveolin-1. PP2A is the key phosphatase involving in tau phosphorylation, which is localized in cholesterol-dependent caveola/raft lipid domains. Here, the PP2A activity was detected by western blot assay. Interestingly, the level of p-PP2Ac at Y307 (inactive) and p-GSK3ß at Y216 (active) in the downstream of the PP2A signal pathway were both significantly increased in silencing DHCR24 SH-SY5Y cells, which denoted an inhibition of the PP2A and activation of GSK3ß signaling. Conversely, overexpression of DHCR24 blunted the inhibition effect of PP2A and activation of GSK3ß. Besides, in the SH-SY5Y cell lines we demonstrated that DHCR24 knockdown obviously induced hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. In contrast, DHCR24 overexpression protects neuronal SH-SY5Y cells against the hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. Furthermore, PP2A activator D-erythro-Sphingosine (DES) also obviously inhibited the hyperphosphorylation of tau induced by DHCR24 knockdown. Collectively, our findings firstly confirmed that DHCR24 knockdown obviously induced abnormal hyperphosphorylation of tau by a novel lipid raft-dependent PP2A signaling. We propose that DHCR24 downregulation led to altered cholesterol synthesis as a potential mechanism in the progression of tau hyperphosphorylation involving in AD and other tauopathies.

Agomelatine Prevents Amyloid Plaque Deposition, Tau Phosphorylation, and Neuroinflammation in APP/PS1 Mice.

Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer's disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-ß (Aß) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.

DHCR24 overexpression modulates microglia polarization and inflammatory response via Akt/GSK3ß signaling in Aß25-35 treated BV-2 cells.

Microglial phenotypic polarization, divided into pro-inflammatory "M1" phenotype and anti-inflammatory "M2" phenotype, played a crucial role in the pathogenesis of Alzheimer's disease (AD). Facilitating microglial polarization from M1 to M2 phenotype was shown to alleviate AD-associate pathologic damage, and modulator of the microglial phenotype has become a promising therapeutic approach for the treatment of AD. Previous little evidence showed that DHCR24 (3-ß-hydroxysteroid-Δ-24-reductase), also known as seladin-1 (selective Alzheimer's disease indicator-1), exerted potential anti-inflammatory property, however, the link between DHCR24 and microglial polarization has never been reported. Thus, the role of DHCR24 in microglial polarization in amyloid-beta 25-35 (Aß25-35) treated BV-2 cells was evaluated in this study. Our results demonstrated that Aß25-35 aggravated inflammatory response and facilitated the transition of microglia phenotype from M2 to M1 in BV-2 cells, by upregulating M1 marker (i-NOS, IL-1ß and TNF-α) and downregulating M2 marker (arginase-1, IL-4 and TGF-ß). DHCR24 overexpression by lentivirus transfection could significantly reverse these effects, meanwhile, activated Akt/GSK3ß signaling pathway via increasing the protein expression of P-Akt and P-GSK3ß. Furthermore, when co-treated with Akt inhibitor MK2206, the effect of DHCR24 was obviously reversed. The study exhibited the neuroprotective function of DHCR24 in AD-related inflammatory injury and provided a novel therapeutic target for AD in the future.

Anti-inflammatory effects of doxepin hydrochloride against LPS-induced C6-glioma cell inflammatory reaction by PI3K-mediated Akt signaling.

Recent studies have shown that tricyclic antidepressants (TCAs) may have anti-inflammatory and anticonvulsant effects in addition to its antidepressant effects. So far, the nonantidepressant effects of TCAs and their molecular pharmacological mechanisms remain completely unclear. Chronic inflammation in the brain parenchyma may be related to the pathogenesis and progression of various neurodegenerative diseases. As a common antidepressant and anti-insomnia drug, doxepin also may be a potential anti-inflammatory and anticonvulsant drug, so the study on the anti-inflammatory protective effect of doxepin and its molecular mechanism has become a very important issue in pharmacology and clinical medicine. Further elucidating the anti-inflammatory and neuroprotective effects of doxepin and its molecular mechanism may provide the important theoretical and clinical basis for the prevention and treatment of neurodegenerative disease. This study was designed to understand the glio-protective mechanism of doxepin against the inflammatory damage induced by lipopolysaccharide (LPS) exposure in C6-glioma cells. We found the treatment of C6-glioma cells with LPS results in deleterious effects, including the augmentation of inflammatory cytokine levels (tumor necrosis factor-α, interleukin-1ß), and suppresses the Akt phosphorylation. Furthermore, our outcomes demonstrated that doxepin was able to suppress these effects induced by LPS, through activation of the phosphatidylinositol-3-kinase-mediated protein kinase B (Akt) pathway. To sum up, these results highlight the potential role of doxepin against neuroinflammatory-related disease in the brain.

Microglial polarization: novel therapeutic mechanism against Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that results in progressive dementia, and exhibits high disability and fatality rates. Recent evidence has demonstrated that neuroinflammation is critical in the pathophysiological processes of AD, which is characterized by the activation of microglia and astrocytes. Under different stimuli, microglia are usually activated into two polarized states, termed the classical 'M1' phenotype and the alternative 'M2' phenotype. M1 microglia are considered to promote inflammatory injury in AD; in contrast, M2 microglia exert neuroprotective effects. Imbalanced microglial polarization, in the form of excessive activation of M1 microglia and dysfunction of M2 microglia, markedly promotes the development of AD. Furthermore, an increasing number of studies have shown that the transition of microglia from the M1 to M2 phenotype could potently alleviate pathological damage in AD. Hence, this article reviews the current knowledge regarding the role of microglial M1/M2 polarization in the pathophysiology of AD. In addition, we summarize several approaches that protect against AD by altering the polarization states of microglia. This review aims to contribute to a better understanding of the pathogenesis of AD and, moreover, to explore the potential of novel drugs for the treatment of AD in the future.

Melatonin receptor stimulation by agomelatine prevents Aß-induced tau phosphorylation and oxidative damage in PC12 cells.

PURPOSE: As a novel antidepressant drug, agomelatine has good therapeutic effect on the mood disorder and insomnia in Alzheimer's disease (AD). Recent studies have shown the neuroprotective function of agomelatine, including anti-oxidative and anti-apoptosis effect. However, it remains unclear whether agomelatine exerts neuroprotection in AD. Thus, the neuroprotective effect of agomelatine against amyloid beta 25-35 (Aß25-35)-induced toxicity in PC12 cells was evaluated in this study. METHODS: The concentration of malondialdehyde (MDA), LDH, and ROS was investigated to evaluate oxidative damage. The expression of P-tau, tau, PTEN, P-Akt, Akt, P-GSK3ß, and GSK3ß proteins was assessed by Western blotting. Our results demonstrated that Aß25-35 significantly increased the content of MDA, LDH, and ROS. Meanwhile, Aß25-35 upregulated the expression of P-tau and PTEN as well as downregulated P-Akt and P-GSK3ß expression. These effects could be blocked by agomelatine pretreatment. Furthermore, luzindole, the melatonin receptor (MT) antagonist, could reverse the neuroprotective effect of agomelatine. CONCLUSION: The results demonstrated that antidepressant agomelatine might prevent the tau protein phosphorylation and oxidative damage induced by Aß25-35 in PC12 cells by activating MT-PTEN/Akt/GSK3ß signaling. This study provided a novel therapeutic target for AD in the future.

Mechanism underlying the effects of doxepin on ß-amyloid -induced memory impairment in rats.

OBJECTIVES: In previous studies, researchers observed that doxepin could improve cognitive processes and has protective effects on the central nervous system. Thus, this study was designed to analyze the effects of doxepin on ß-amyloid (Aß)-induced memory impairment and neuronal toxicity in rat and to explore the underlying mechanism. MATERIALS AND METHODS: Rats were treated with Aß1-42 and doxepin was injected to validate its effects on cognitive function. The Morris water maze test was performed to detect memory function. Aß1-42-treated SH-SY5Y human neuroblastoma cell line was also used to detect the effects of doxepin and to explore the underlying mechanism. Western blotting analysis was used to detect the protein expression levels of PSD-95, synapsin 1, p-AKT and p-mTOR in rats. RESULTS: After treated with 1 mg/kg of doxepin, Aß1-42-treated rats showed markedly lower escape latency and higher platform-finding strategy score. Low doses of doxepin significantly reversed the effects of Aß1-42 on the protein expression levels of PSD-95, synapsin 1, p-AKT and p-mTOR in rats. In vitro experiment showed the consistent results. Besides, PI3K inhibitor (LY294002) treatment could markedly reversed the effects of doxepin on Aß1-42-treated SH-SY5Y cells. CONCLUSION: Our results demonstrated that doxepin could protect against the Aß1-42-induced memory impairment in rats. The protective effect of doxepin was associated with the enhancement of PSD-95 and synapsin 1 expression via PI3K/AKT/mTOR signaling pathway.

Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks. Our data showed that intranasal BMP9 administration significantly improved the spatial and associative learning and memory of APP/PS1 mice. We also found that intranasal BMP9 administration significantly reduced the amyloid ß (Aß) plaques overall, inhibited tau hyperphosphorylation, and suppressed neuroinflammation in the transgenic mouse brain. Furthermore, intranasal BMP9 administration significantly promoted the expression of low-density lipoprotein receptor-related protein 1 (LRP1), an important membrane receptor involved in the clearance of amyloid ß via the blood-brain barrier (BBB), and elevated the phosphorylation levels of glycogen synthase kinase-3ß (Ser9), which is considered the main kinase involved in tau hyperphosphorylation. Our results suggest that BMP9 may be a promising candidate for treating AD by targeting multiple key pathways in the disease pathogenesis.

Insulin-like growth factor-1 protects SH-SY5Y cells against ß-amyloid-induced apoptosis via the PI3K/Akt-Nrf2 pathway.

Insulin-like growth factor-1 (IGF-1) shows protective effect against Aß-induced cytotoxicity and apoptosis, but the underlying mechanisms are poorly characterized. The present study was conducted to explore the mechanisms involved in the beneficial effect of IGF-1 against Aß-induced apoptosis in SH-SY5Y cells. We found that pretreatment with IGF-1 attenuated Aß25-35-induced loss of cell viability and apoptosis in SH-SY5Y cells in a dose-dependent manner. In addition, IGF-1 inhibited the generation of reactive oxygen species (ROS) and increased the antioxidant activity in Aß25-35-treated cells. Further, IGF-1 significantly promoted the nuclear translocation of Nrf2, and upregulated the expression of its downstream gene heme oxygenase-1 (HO-1). Moreover, LY294002, a specific PI3K inhibitor, was found to completely abolish the protective effect of IGF-1 on Aß25-35-induced apoptosis and ROS generation. Together, our findings suggest that IGF-1 protects SH-SY5Y cells against Aß25-35-induced cell injury by scavenging ROS via the PI3K/Akt-Nrf2 signaling pathway.