Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain.

Neuropathic pain (NPP) remains a clinically challenging condition, driven by the activation of spinal astrocytes and the complex release of inflammatory mediators. This study aimed to examine the roles of Rab8a and SNARE complex proteins in activated astrocytes to uncover the underlying mechanisms of NPP. The research was conducted using a rat model with chronic constriction injury (CCI) of the sciatic nerve and primary astrocytes treated with lipopolysaccharide. Enhanced expression of Rab8a was noted specifically in spinal dorsal horn astrocytes through immunofluorescence. Electron microscopy observations showed increased vesicular transport and exocytic activity in activated astrocytes, which was corroborated by elevated levels of inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α detected through quantitative PCR. Western blot analyses confirmed significant upregulation of Rab8a, VAMP2, and Syntaxin16 in these cells. Furthermore, the application of botulinum neurotoxin type A (BONT/A) reduced the levels of vesicle transport-associated proteins, inhibiting vesicular transport in activated astrocytes. These findings suggest that the Rab8a/SNARE pathway in astrocytes enhances vesicle transport and anchoring, increasing the secretion of bioactive molecules that may play a crucial role in the pathophysiology of NPP. Inhibiting this pathway with BONT/A offers a novel therapeutic target for managing NPP, highlighting its potential utility in clinical interventions.

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aß accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

MKP-1 regulates the inflammatory activation of microglia against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia in elderly people. Microglia-mediated neuroinflammation plays an important role in AD pathogenesis, so modulation of neuroinflammation has emerged as an essential therapeutic method to improve AD. The current study aims to investigate whether MKP-1 can regulate microglia phenotype and inflammatory factor release in AD and explore its possible mechanisms. METHODS: Amyloid precursor protein/PS1 double transgenic mice and wild-type mice were selected to study the locations of microglia and amyloid-ß (Aß) plaques in different regions of mice brains. Changes in MKP-1 of microglia were detected using AD model mice and AD model cells. Changes in phenotype and the release of inflammatory factors within immortalized BV2 murine microglia were investigated by regulating the expression of MKP-1. RESULTS: The distribution of microglia and Aß plaques in the AD brain was region-specific. MKP-1 expression was downregulated in AD mice, and in vitro, with increasing Aß concentrations, MKP-1 expression was reduced. MKP-1 over-expression increased M2 microglia but decreased M1 microglia accompanied by changes in inflammatory factors and inhibition of MKP-1 yielded the opposite result. CONCLUSION: MKP-1 regulated microglia phenotype and inflammatory factor release in AD through modulation of the p38 signaling pathway.

The functional role of lncRNAs as ceRNAs in both ovarian processes and associated diseases.

Long non-coding RNAs (lncRNAs) have attracted significant scientific attention due to their central role in regulating gene expression and their profound impact on the intricate mechanisms of ovarian function. These versatile molecules exert their influence through various mechanisms, including the coordination of transcription processes, modulation of post-transcriptional events, and the shaping of epigenetic landscapes. Furthermore, lncRNAs function as competitive endogenous RNAs (ceRNAs), engaging in intricate interactions with microRNAs (miRNAs) to finely adjust the expression of target genes. The intricate lncRNA-miRNA-mRNA network serves as a crucial determinant in governing the multifaceted physiological functions of the ovaries. It holds substantial potential in unraveling the causes and progression of reproductive disorders and, importantly, in identifying new therapeutic targets and diagnostic markers for these conditions. A comprehensive comprehension of lncRNAs and their ceRNA activities within the domain of ovarian biology could potentially lead to groundbreaking advancements in clinical interventions and management strategies. This exploration of lncRNAs and their intricate involvement in the regulatory framework provides an extensive platform for deciphering the complex nature of ovarian physiology and pathology. The ongoing progress in this field, which encompasses in-depth investigations into the functional roles of specific lncRNAs, the elucidation of their complex interactions with miRNAs, and the comprehensive profiling of their expression patterns, holds the promise of making significant contributions to our understanding of ovarian biology and reproductive disorders. Ultimately, these breakthroughs will have wide-ranging translational implications, paving the way for the development of precision therapies and personalized medicine strategies to address the myriad challenges in the realm of reproductive health.

Intestinal changes in permeability, tight junction and mucin synthesis in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid­ß (Aß) in the brain. The gut/brain axis may serve a role in AD pathogenesis. The present study investigated deposition of Aß in the intestinal epithelium and its potential effects on intestinal barrier function in a transgenic mouse model of AD. To investigate alterations in the structure and functionality of the intestinal mucosal barrier in AD model mice, hematoxylin and eosin staining for Paneth cell count, Alcian blue­periodic acid Schiff staining for goblet cells, immunohistochemistry and immunofluorescence for mucin (MUC)2 and wheat germ agglutin expression, transmission electron microscopy for mucosal ultrastructure, FITC­labeled dextran assay for intestinal permeability, quantitative PCR for goblet cell precursor expression and western blot analysis for tight junction proteins, MUC2 and inflammatory cytokine detection were performed. The results showed that AD model mice exhibited excessive Aß deposition in the intestinal epithelium, which was accompanied by increased intestinal permeability, inflammatory changes and decreased expression of tight junction proteins. These alterations in the intestinal barrier led to an increased proliferation of goblet and Paneth cells and increased mucus synthesis. Dysfunction of gut barrier occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve early manipulation of gut physiology and its microbiota.

Structure, function, and pathology of Neurexin-3.

Neurexin-3 is primarily localized in the presynaptic membrane and forms complexes with various ligands located in the postsynaptic membrane. Neurexin-3 has important roles in synapse development and synapse functions. Neurexin-3 mediates excitatory presynaptic differentiation by interacting with leucine-rich-repeat transmembrane neuronal proteins. Meanwhile, neurexin-3 modulates the expression of presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors and γ-aminobutyric acid A receptors by interacting with neuroligins at excitatory and inhibitory synapses. Numerous studies have documented the potential contribution of neurexin-3 to neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease, addiction behaviors, and other diseases, which raises hopes that understanding the mechanisms of neurexin-3 may hold the key to developing new strategies for related illnesses. This review comprehensively covers the literature to provide current knowledge of the structure, function, and clinical role of neurexin-3.

Liquiritigenin promotes osteogenic differentiation and prevents bone loss via inducing auto-lysosomal degradation and inhibiting apoptosis.

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro, and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP.

Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice.

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERß-mediated IGF-1/IGF-1R/GSK-3ß signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

Decreased expression of protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 contributes to Alzheimer's disease-like pathologies.

Alzheimer's disease (AD) is pathologically characterized by senile plaques and neurofibrillary tangles composed of ß-amyloid peptide (Aß) and tau hyperphosphorylation, respectively. Mannosylation, a particular type of posttranslational modification, may be involved in the pathogenesis of AD. However, its underlying mechanism remains unclear. Protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) catalyzes the formation of the N-acetylglucosamine ß-1,2-Man linkage of O-mannosylglycan, which can increase the protein posttranslational mannosylation level. The defective POMGnT1 gene leads to the hypomannosylation of proteins, which may cause cognitive decline in aged people. This study aimed to investigate whether POMGnT1 participated in the pathogenesis of AD and explore its underlying role using AD mouse and cell models. In this study, the expression of POMGnT1 was measured in AD models [ß-amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, an AD mouse model; N2a cells stably transfected with Swedish mutant APP (N2a/APP), an AD cell model]. The results revealed that the expression of POMGnT1 decreased in AD mouse and cell models. In addition, POMGnT1-overexpressing N2a/APP cells were built by retroviral transfection. POMGnT1 overexpression may lower Aß levels by reducing APP production and downregulating ß- and γ-secretase activities. It also promoted clearance of Aß by upregulating insulin-degrading enzymes and ameliorated tau hyperphosphorylation. Hence, it was concluded that POMGnT1 was involved in the pathogenic process of AD. The decreased expression of POMGnT1 contributes to AD-like pathologies.NEW & NOTEWORTHY This study explored the role of mannosylation in the pathogenesis of AD through a mannosyltransferase-POMGnT1. Results demonstrated that target gene overexpression could ameliorate pathologies of Aß and tau hyperphosphorylation. This study is the first to examine the relationship between mannosylation and AD.

Optogenetic stimulation of CA3 pyramidal neurons restores synaptic deficits to improve spatial short-term memory in APP/PS1 mice.

The hippocampal CA3 region, that is involved in the encoding and retrieval of spatial memory, is found to be synaptically impaired in the early-onset of Alzheimer's disease (AD). It is reported optogenetic manipulation of DG or CA1 can rescue the memory impairment of APP/PS1 mice, however, how CA3 region contributes to AD-related deficits in cognitive function is still unknown. Our work shows optogenetic stimulation of CA3 pyramidal neurons (PNs) significantly restores the impaired spatial short-term memory of APP/PS1 mice. This enhances the anatomical synaptic density/strength and synaptic plasticity as well as activates astrocytes. Chemogenetic inhibiting the activity of CA3 astrocytes reverses the effect of optogenetic stimulation of CA3 PNs that leads to reduced anatomical synaptic density/strength, decreased synaptic protein and AMPA receptors GluA3/4, thus disrupting the cognitive restoration of APP/PS1 mice. These results reveal the molecular mechanism of optogenetic activation of CA3 PNs on restoration of the spatial short-term memory of APP/PS1 mice and unveil a potential strategy of manipulating CA3 for AD treatment.

Analysis of the expression and distribution of protein O-linked mannose ß1,2-N-acetylglucosaminyltransferase 1 in the normal adult mouse brain.

Introduction: Protein O-linked mannose ß1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is crucial for the elongation of O-mannosyl glycans. Mutations in POMGNT1 cause muscle-eye-brain (MEB) disease, one of the main features of which is anatomical aberrations in the brain. A growing number of studies have shown that defects in POMGNT1 affect neuronal migration and distribution, disrupt basement membranes, and misalign Cajal-Retzius cells. Several studies have examined the distribution and expression of POMGNT1 in the fetal or neonatal brain for neurodevelopmental studies in the mouse or human brain. However, little is known about the neuroanatomical distribution and expression of POMGNT1 in the normal adult mouse brain. Methods: We analyzed the expression of POMGNT1 mRNA and protein in the brains of various neuroanatomical regions and spinal cords by western blotting and RT-qPCR. We also detected the distribution profile of POMGnT1 in normal adult mouse brains by immunohistochemistry and double-immunofluorescence. Results: In the present study, we found that POMGNT1-positive cells were widely distributed in various regions of the brain, with high levels of expression in the cerebral cortex and hippocampus. In terms of cell type, POMGNT1 was predominantly expressed in neurons and was mainly enriched in glutamatergic neurons; to a lesser extent, it was expressed in glial cells. At the subcellular level, POMGNT1 was mainly co-localized with the Golgi apparatus, but expression in the endoplasmic reticulum and mitochondria could not be excluded. Discussion: The present study suggests that POMGNT1, although widely expressed in various brain regions, may has some regional and cellular specificity, and the outcomes of this study provide a new laboratory basis for revealing the possible involvement of POMGNT1 in normal physiological functions of the brain from a morphological perspective.

Allergic Asthma-Induced Cognitive Impairment is Alleviated by Dexamethasone.

Allergic asthma is a typical chronic inflammatory disease of respiratory tract. Clinical data shows that patients with allergic asthma have different degrees of cognitive dysfunction. The molecular mechanism underlying the pathogenesis of asthma-induced cognitive disorder is not yet well defined. Dexamethasone (DEX), one of the first-line drugs being widely used in the treatment of asthma, has not been reported to have an effect on cognitive dysfunction in mice model. To investigate the effect of asthma on cognitive impairment as well as the effect of DEX on asthma-caused morphological and behavioral changes, C57BL/6J mice received treatment with house dust mites (HDM) for 60 days to become allergic asthma model mice, and a group of HDM-treated asthma model mice were treated with DEX. HDM-treated asthma model mice exhibited increased airway hyperresponsiveness (AHR) and inflammatory infiltration in lung tissue. An elevated level of IL-4, IL-5, and TNF-α was detected in bronchoalveolar lavage fluid (BALF) by Luminex liquid suspension chip. Asthma model mice also presented memory deficits accompanied with morphological changes at the synaptic levels in the cortex and hippocampus. Meanwhile, vascular edema and increased expression of HIF-1α and HIF-2α were found in the brain of asthma model mice. Interestingly, DEX treatment could reverse the inflammatory changes in asthma model mice airway, rescue the cognitive impairment and improve the synaptic plasticity. Besides, DEX significantly decreased the expression of HIF-1α and HIF-2α in mice brain and lung. These processes may be used to decipher the complex interplay and pathological changes between asthma and cognition. This study provides laboratory evidence for the prevention and treatment of cognitive malfunction induced by asthma.

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates.

The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.

Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid ß peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aß25-35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1ß, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aß25-35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aß25-35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.

Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer's disease.

Postmenopausal women with Alzheimer's disease (AD) exhibit dramatically reduced sensitivity to estrogen replacement therapy, which is though to be related to an estrogen receptor (ER)α/ERß ratio imbalance arising from a significantly decreased level of ERs of the brain. The aim of our study was to investigate whether valproic acid (VPA) can enhance the beneficial effects of estrogen on cognitive function through restoration of ERα and ERß expression in the brain. We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA (30 mg/kg, intraperitoneal injection, once daily), 17ß-estradiol (E2) (2.4 µg, intraperitoneal injection, once daily), liquiritigenin (LG) (50 µg/kg, intragastric infusion, once daily), VPA + E2, or VPA + LG for 4 successive weeks. Compared with treatment with a single drug, treatment with VPA + E2 or VPA + LG significantly increased the level of glycogen synthase kinase 3ß, increased the expression of estrogen receptor α, reduced the expression of small ubiquitin-like modifiers, and increased the level of estrogen receptor ß. This resulted in enhanced sensitivity to estrogen therapy, reduced amyloid ß aggregation, reduced abnormal phosphorylation of the tau protein, reduced neuronal loss, increased dendritic spine and postsynaptic density, and significantly alleviated memory loss and learning impairment in mice. This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee, China on March 6, 2013.

Liquiritigenin Decreases Aß Levels and Ameliorates Cognitive Decline by Regulating Microglia M1/M2 Transformation in AD Mice.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is currently incurable. Amyloid ß protein (Aß) deposition is the main pathogenesis of AD, and many studies have shown that Aß accumulation is toxic to neurons, leading to the inflammatory reaction, neuronal apoptosis, and neurofibrillary tangles. Thus, reducing Aß levels might be a potential therapeutic strategy for AD. Liquiritigenin (LG), a dihydroflavone monomer compound extracted from natural plant licorice, has a variety of biological activities such as antioxidant, anti-tumor, anti-inflammatory and anti-virus. However, the exact function of LG in the pathogenesis of AD is elusive. Here, we reported that LG could significantly attenuate neuronal apoptosis in Aß-induced N2A cells and APP/PS1 transgenic mice. Our in vivo and in vitro studies revealed that LG could alleviate the inflammation response, reflected by the reduction of NLRP3 and cleaved caspase-1. Meanwhile, we also found that LG was able to shift M1 type microglia towards M2 type microglia in Aß-induced BV2 cells and AD mice. Furthermore, LG could reduce the Aß levels by decreasing APP processing and accelerating Aß clearance in AD mice. More importantly, daily treatment of LG (30 mg/kg day) for 90 days dramatically ameliorated the spatial learning and memory of AD mice. Taken together, these results suggest that LG can reduce the Aß levels by regulating the M1/M2 transformation of microglia, thereby reversing memory decline during AD development, suggesting that LG may be a potential therapeutic agent for treating AD.

Dihydroartemisinin Ameliorates Decreased Neuroplasticity-Associated Proteins and Excessive Neuronal Apoptosis in APP/PS1 Mice.

BACKGROUND: Alzheimer's disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aß clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro. METHODS: The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax. In parallel, the expression of the anti-apoptotic protein Bcl-2 increased after oral DHA treatment. RESULTS: Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis.

Dynamic changes of autophagic flux induced by Abeta in the brain of postmortem Alzheimer's disease patients, animal models and cell models.

Autophagy has been reported to play a dual "double-edged sword" role in the occurrence and development of Alzheimer's disease (AD). To assess the relationship between AD and autophagy, the dynamic changes of autophagic flux in the brain of postmortem AD patients, animal models and cell models were studied. The results showed that autophagosomes (APs) accumulation and expression of lysosomal markers were decreased in the brains of AD patients. In the brain of APP/PS1 double transgenic mice, APs did not accumulate before the formation of SPs but accumulated along with the deposition of SPs, as well as the level of lysosomal markers cathepsin B and Lamp1 protein decreased significantly. In the brains of APP/PS1/LC3 triple - transgenic mice, the number of APs increased with age, but the number of ALs did not increase accordingly. The activation of autophagy is mainly due to the increase in Aß rather than the overexpression of mutated APP gene. However, both the treatment with exogenous Aß25-35 and the mutation of the endogenous APP gene blocked the fusion of APs with lysosomes and decreased lysosomal functioning in AD model cells, which may be the main mechanism of autophagy dysregulation in AD.

Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells.

Gene regulation and metabolism are two fundamental processes that coordinate the self-renewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain. However, little is known about how metabolic signals instruct gene expression to control NPC homeostasis. Here, we show that methylglyoxal, a glycolytic intermediate metabolite, modulates Notch signalling to regulate NPC fate decision. We find that increased methylglyoxal suppresses the translation of Notch1 receptor mRNA in mouse and human NPCs, which is mediated by binding of the glycolytic enzyme GAPDH to an AU-rich region within Notch1 3'UTR. Interestingly, methylglyoxal inhibits the enzymatic activity of GAPDH and engages it as an RNA-binding protein to suppress Notch1 translation. Reducing GAPDH levels or restoring Notch signalling rescues methylglyoxal-induced NPC depletion and premature differentiation in the developing mouse cortex. Taken together, our data indicates that methylglyoxal couples the metabolic and translational control of Notch signalling to control NPC homeostasis.