Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

[Chronic sleep deprivation exacerbates cognitive and pathological impairments in APP/PS1/tau triple transgenic Alzheimer's disease model mice].

Sleep exerts important functions in the regulation of cognition and emotion. Recent studies have found that sleep disorder is one of the important risk factors for Alzheimer's disease (AD), but the effects of chronic sleep deprivation on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1/tau triple transgenic AD model (3xTg-AD) mice and wild type (WT) mice (n = 8 for each group) were subjected to chronic sleep deprivation by using the modified multiple platform method, with 20 h of sleep deprivation each day for 21 days. Then, open field test, elevated plus maze test, sugar water preference test, object recognition test, Y maze test and conditioned fear memory test were performed to evaluate anxiety- and depression-like behaviors, and multiple cognitive functions. In addition, the immunohistochemistry technique was used to observe pathological characteristics in the hippocampus of mice. The results showed that: (1) Chronic sleep deprivation did not affect anxiety- (P = 0.539) and depression-like behaviors (P = 0.874) in 3xTg-AD mice; (2) Chronic sleep deprivation exacerbated the impairments of object recognition memory (P < 0.001), working memory (P = 0.002) and the conditioned fear memory (P = 0.039) in 3xTg-AD mice; (3) Chronic sleep deprivation increased amyloid ß (Aß) deposition (P < 0.001) and microglial activation (P < 0.001) in the hippocampus of 3xTg-AD mice, without inducing abnormal tau phosphorylation and neurofibrillary tangles. These results indicate that chronic sleep deprivation exacerbates the impairments of recognition memory, working memory and conditioned fear memory in 3xTg-AD mice by aggravating Aß deposition and the excessive activation of microglia in the hippocampus.

A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aß1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aß plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3ß levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aß and normalization of PI3K/AKT/GSK3ß cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.

A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-ß (Aß) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3ß in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

Amyloid ß protein injection into medial septum impairs hippocampal long-term potentiation and cognitive behaviors in rats.

The specific loss of cholinergic neurons and the progressive deficits of cognitive function are the most primary characteristics of Alzheimer's disease (AD). Although the neurotoxicity of amyloid ß protein (Aß) in AD has been investigated extensively, it is still unclear whether the Aß aggregated in the medial septum (MS), a major cholinergic nucleus projecting to the hippocampus, could affect hippocampal synaptic plasticity and further impair the memory behaviors. The present study investigated the effects of Aß injection into the MS on hippocampal long-term potentiation (LTP) and cognitive behaviors of rats by using Morris water maze (MWM), Y maze and in vivo hippocampal LTP recording. The effects of kainic acid (KA), an agent with specific neurotoxicity to GABAergic neurons, were also observed. The results showed that: (1) Intra-MS injection of Aß25-35, not KA, impaired spatial learning and memory of rats in classical and reversal MWM tests; (2) Both Aß25-35 and KA impaired novelty-seeking behavior of rats in Y maze; (3) Intra-MS injection of Aß25-35, not KA, suppressed in vivo hippocampal LTP in the CA1 region of rats; (4) Both Aß25-35 and KA did not affect the motor ability in behavioral tests and the hippocampal paired-pulse facilitation (PPF) in electrophysiological recording. These results indicate that intra-MS injection of Aß could impair spatial memory, cognitive flexibility and exploratory motivation, as well as hippocampal LTP in rats, suggesting that the cholinergic neurons in the MS and the septo-hippocampal projection could be important targets of neurotoxic Aß, and the specific damage of cholinergic neurons in the MS is likely responsible for the impairments of hippocampal synaptic plasticity and cognitive function in AD.

High-intensity treadmill running impairs cognitive behavior and hippocampal synaptic plasticity of rats via activation of inflammatory response.

Although appropriate exercise is beneficial for enhancing brain functions, high-intensity exercise (HIE)-induced cognitive dysfunction is causing more and more concerns nowadays. In the present study, we observed the effects of high-intensity treadmill running on the spatial learning of the adult Sprague Dawley male rats in Y-maze (n = 16 per group), and investigated its possible electrophysiological and molecular mechanisms by examining in vivo hippocampal long-term potentiation (LTP), central inflammatory responses, and JNK/p38/ERK signal pathway. The Y-maze active avoidance test showed that high-intensity treadmill running impaired spatial learning ability of rats, with increased error times and prolonged training time in recognizing safety condition. Associated with the cognitive dysfunction, the induction and maintenance of hippocampal LTP were also impaired by the HIE. Furthermore, accompanied by elevated levels of inflammatory factors IL-1ß, TNF-α, and iNOS, overactivation of microglia and astrocytes was also found in the CA1 region of hippocampus in the excessive exercise group, indicating an inflammatory response induced by HIE. In addition, Western blot assay showed that the phosphorylation of JNK/p38/ERK proteins was enhanced in the exercise group. These results suggest that exercise stress-induced neuronal inflammatory responses in the hippocampus are associated with HIE-induced cognitive deficits, which may be involved in the upregulation of the JNK/p38/ERK pathway. © 2016 Wiley Periodicals, Inc.

[GLP-1/GIP/Gcg receptor Triagonist improves the cognitive behaviors in triple-transgenic mice of Alzheimer's disease].

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.

Desipramine improves depression-like behavior and working memory by up-regulating p-CREB in Alzheimer's disease associated mice.

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

[Neuroprotective effects of a novel antidiabetic drug (D-Ser2)Oxm on amyloid ß protein-induced cytotoxicity].

The accumulation and neurotoxicity of amyloid ß protein (Aß) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aß have been still deficient up to now. According to a most recent study, (D-Ser2) Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aß1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aß1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aß1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aß1-42-induced [Ca(2+)]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3ß (GSK3ß) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aß1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential.

Colivelin ameliorates amyloid ß peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats.

Amyloid ß peptide (Aß) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD-related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Aß by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Aß25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aß25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aß25-35-induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Aß, and CLN may holds great promise for the treatment and prevention of AD.

Leptin attenuates the detrimental effects of ß-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats.

ß-Amyloid (Aß) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aß in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aß-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1µg) effectively alleviated Aß1-42 (20µg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aß1-42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aß-induced deficits in learning and memory and the maintenance of L-LTP.

[Amyloid ß protein suppresses hippocampal theta rhythm and induces behavioral disinhibition and spatial memory deficit in rats].

Hippocampal neuronal network oscillation is closely related to the memory, anxiety and behavioral inhibition of mammalian. The cognitive decline and behavioral disinhibition in the patients with Alzheimer's disease (AD) may be relevant to amyloid ß protein (Aß)-induced impairment in hippocampal neuronal cooperative activity. However, it is not well known whether intrahippocampal injection of Aß could induce behavioral disinhibition and neuronal network disorder, as well as cognition decline in animals. In the present study, we observed the effects of intracerebral injection of Aß(1-42) on the spatial memory and behavioral inhibition of rats by using Morris water maze and elevated plus-maze tests. Further, we analyzed hippocampal theta rhythm by recording hippocampal local field potential. The results showed that: (1) bilateral hippocampal injection of Aß(1-42) reduced the anxious behavior of rats, with a significant behavioral disinhibition in the elevated plus-maze test, representing as an increase in the mean entering times and mean residence time in the open arm; (2) Aß(1-42) injection resulted in a significant impairment of spatial memory in rats, with significantly increased mean escape latencies in hidden platform test; (3) Aß(1-42) disrupted the induction of theta rhythm induced by tail pinch, with a significant reduction in the peak power, not the peak power frequency of the theta rhythm. These experimental results indicate that intrahippocampal injection of Aß(1-42) can induce behavioral disinhibition and theta rhythm suppression, as well as spatial memory impairment in rats, which suggests that the cognition deficits and behavior impairments in AD are probably associated with the Aß-induced disruption of hippocampal theta rhythm and consequent down-regulation of synaptic plasticity.

Mitochondrial calcium uniporter knockdown in hippocampal neurons alleviates anxious and depressive behavior in the 3XTG Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABAA receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Amyloid ß-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons.

Amyloid ß protein (Aß) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aß and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aß-induced damage of nAChRs. This study investigated the effects of Aß fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4ß2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-µM) of Aß25-35, Aß31-35, or Aß35-31 alone did not trigger any membrane current, but pretreatment with 1 µM Aß25-35 and Aß31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine-induced currents were also reversibly suppressed by the Aß pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both α7 and α4ß2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aß treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aß in AD. In addition, the similar suppression of nAChR currents by Aß25-35 and Aß31-35 suggests that the sequence 31-35 in Aß molecule may be a shorter active center responsible for the neurotoxicity of Aß in AD.

[Prognosis related clinical and molecular factors in malignant pleural mesothelioma].

OBJECTIVE: To identify potential prognosis related clinical and molecular factors in malignant pleural mesothelioma (MPM). METHODS: Seventy-nine patients with MPM treated in Beijing Cancer Hospital from June 1996 to May 2012 were enrolled in this study. Clinical and pathological data were collected, including age, gender, smoking status, treatment, response, and molecular biomarkers such as thymidylate synthetase (TS) expression, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene rearrangement. The primary endpoint was overall survival (OS). SPSS 16.0 statistical analysis software was used for univariate analysis. The expression of TS was detected by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) was performed to detect EML4-ALK gene rearrangement. Efficacy of the chemotherapy regimen including pemetrexed was analyzed with these molecular biomarkers. RESULTS: The median survival time (MST) of all patients was 15.5 months (95% CI: 10.6 - 20.4). Univariate survival analysis revealed that treatment factors including receiving operation, systemic chemotherapy, pemetrexed-based chemotherapy and capability of receiving second (or above) line chemotherapy were significantly related with OS. The MST of patients receiving operation was 5.4 months (95% CI: 3.6 - 7.3), significantly shorter than the 17.7months (95% CI: 11.8 - 23.5) in those who didn't receive operation (P = 0.030). Patients receiving systemic chemotherapy had a longer MST of 18.0 months (95% CI: 12.3 - 23.8) as compared to the 7.9 months (95% CI: 1.1 - 14.7) in those who didn't (P = 0.001). The MST of pemetrexed-based chemotherapy was 21.9 months (95% CI: 14.1-29.7) compared with 8.8 months (95% CI: 4.2 - 13.4) of regimens without pemetrexed (P = 0.000). For patients capable of receiving second (or above) line chemotherapy the MST was longer (21.0 months, 95% CI: 12.7 - 29.3) than those who could not (12.1 month, 95% CI: 6.4 - 17.8 month), P = 0.022. For the 42 patients treated with pemetrexed-based chemotherapy, the objective response rate (ORR) was 33.3% (14/42), the disease control rate (DCR) was 78.6% (33/42), the median progression-free survival (PFS) was 4.8 months (95% CI: 3.6 - 6.0) and MST was 21.9 months (95% CI: 14.1 - 29.7). Twenty-nine patients provided adequate specimens for detection of TS expression and 6 cases (20.7%) were positive. EML4-ALK gene rearrangement was studied in 32 patients and 6 (18.8%) were positive. TS expression was found to be inversely related to PFS of pemetrexed-based chemotherapy (P = 0.041). The MST was 19.6 months (95% CI: 6.0 - 7.9) in EML4-ALK-positive patients and 9.57 months (95% CI: 2.7 - 4.3) in negative ones (P = 0.159). CONCLUSIONS: Systemic chemotherapy especially pemetrexed-based regimen was proved to be a superior option for MPM with a significantly prolonged OS. Correlation between TS expression or EML4-ALK rearrangement and outcome of pemetrexed-based chemotherapy for MPM may contribute to future individualized treatment, which needs further validation from large-scale prospective studies.

Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Selective orexin 1 receptor antagonist SB-334867 aggravated cognitive dysfunction in 3xTg-AD mice.

Cognitive dysfunction is the main clinical manifestation of Alzheimer's disease (AD). Previous research found that elevated orexin level in the cerebrospinal fluid was closely related to the course of AD, and orexin-A treatment could increase amyloid ß protein (Aß) deposition and aggravate spatial memory impairment in APP/PS1 mice. Furthermore, recent research found that dual orexin receptor (OXR) antagonist might affect Aß level and cognitive dysfunction in AD, but the effects of OX1R or OX2R alone is unreported until now. Considering that OX1R is highly expressed in the hippocampus and plays important roles in learning and memory, the effects of OX1R in AD cognitive dysfunction and its possible mechanism should be investigated. In the present study, selective OX1R antagonist SB-334867 was used to block OX1R. Then, different behavioral tests were performed to observe the effects of OX1R blockade on cognitive function of 3xTg-AD mice exhibited both Aß and tau pathology, in vivo electrophysiological recording and western blot were used to investigate the potential mechanism. The results showed that chronic OX1R blockade aggravated the impairments of short-term working memory, long-term spatial memory and synaptic plasticity in 9-month-old female 3xTg-AD mice, increased levels of soluble Aß oligomers and p-tau, and decreased PSD-95 expression in the hippocampus of 3xTg-AD mice. These results indicate that the detrimental effects of SB-334867 on cognitive behaviors in 3xTg-AD mice are closely related to the decrease of PSD-95 and depression of in vivo long-term potentiation (LTP) caused by increased Aß oligomers and p-tau.

Agomelatine: a potential novel approach for the treatment of memory disorder in neurodegenerative disease.

Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B (MT1/MT2) and antagonist of 5-hydroxytryptamine 2C receptors. It is used clinically to treat major depressive episodes in adults. The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B, which work simultaneously to counteract depression and anxiety disorder. Moreover, by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors, agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex, increases the activity of dopamine and noradrenaline, and thereby reduces depression and anxiety disorder. The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression, anxiety, and disturbance of the circadian rhythm. Emotion and sleep are closely related to memory and cognitive function. Memory disorder is defined as any forms of memory abnormality, which is typically evident in a broad range of neurodegenerative diseases, including Alzheimer's disease. Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases. Therefore, whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research "hotspot". This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments. Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.