Neuronal Damage Research Articles

Severity of Repetitive Mild Traumatic Brain Injury Depends on Microglial Heme Oxygenase-1 and Carbon Monoxide.

Traumatic brain injury is one of the most common cerebral incidences worldwide. Repetitive mild traumatic brain injuries occurring, for example, in athletes or victims of abuse, can cause chronic neurodegeneration due to neuroinflammation, in which the crosstalk between reactive astrocytes and activated microglia is crucial for modulating neuronal damage. The inducible enzyme heme oxygenase-1 and its product carbon monoxide are known to be ascribed neuroprotective and anti-inflammatory properties. We caused repetitive mild traumatic brain injuries in wild-type mice compared to mice without microglial heme oxygenase-1 expression. Additionally, mice were treated daily with either air or carbon monoxide exogenously. In wild-type mice, we observed enhanced microglia activation and astrogliosis as well as vasodilation after repetitive trauma. In heme oxygenase-1 knockout mice, we observed enhanced activation of microglia and astrocytes at baseline pretrauma with a lack of an adequate inflammatory response to repetitive injury. However, the knockout led to enhanced NF-κB and IFNγ expression in the post-trauma period. Carbon monoxide exerted neuroprotection, as suggested by reduced wake-up times in mice and by beneficially altering inflammation post-traumatic brain injury. This study further underlines the crucial role of the heme oxygenase-1/carbon monoxide system in the modulation of neuronal damage and the associated neuroinflammatory response after repetitive traumatic brain injury.

Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives.

Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.

Upregulation of cAMP/PKA/CREB signaling mediated by GABABR might contribute to the amelioration effects of sea cucumber peptides (Acaudina leucoprocta) on cognitive dysfunction in mice

This study aimed to determine the effects and underlying mechanisms of sea cucumber peptides (SCP) obtained from Acaudina leucoprocta in mitigating induced by D-galactose cognitive dysfunction in mice. Additionally, it aimed to validate the cognitive-enhancing potential of peptides identified via in silico and peptidomics using SH-SY5Y cells. The results demonstrated significant improvement in behavioral performance with oral administration of SCP. Additionally, SCP normalized oxidative stress and neurotransmitter imbalances (especially gamma-aminobutyric acid, GABA). Also, SCP effectively rectified gut microbiota dysbiosis. Mechanistically, SCP activated the γ-aminobutyric acid type B receptors (GABABR)/ cyclic adenosine monophosphate (cAMP)/ cAMP-dependent protein kinase A (PKA)/ cAMP response element-binding protein (CREB) axis to promote GABA release and alleviate neuronal and oxidative stress damage, which subsequently ameliorated cognitive dysfunction. Furthermore, docking analysis predicted the binding of fourteen peptides with high abundance and PeptideRanker scores to GABABR. Notably, Lys-Gly-Phe-Pro (KGFP) had the strongest binding affinities and actively interacted with GABABR sites through hydrogen bonds, van der Waals, hydrophobic, and electrostatic interactions. The capacity of KGFP to improve cognitive function was further demonstrated when the SH-SY5Y cells were subjected to D-galactose. These results imply that the implementation of SCP intervention could be a useful tactic for improving cognitive function.

Long non-coding RNA OIP5-AS1 protects neurons from ischemia-reperfusion injury and inhibits neuronal apoptosis through TAB-2.

Ischemic stroke represents a highly perilous cerebrovascular disorder, involving a variety of complex pathophysiological mechanisms. OIP5 antisense RNA 1 (OIP5-AS1) is a long non-coding RNA (LncRNA) that has been shown to play a pivotal role in a variety of disease systems. However, there are relatively few studies on ischemic stroke. This research aimed to elucidate the direct impact of OIP5-AS1 on neuronal cells following cerebral ischemia-reperfusion. Our study revealed a significant reduction in OIP5-AS1 expression in mouse neurons following middle cerebral artery occlusion/reperfusion (MCAO/R). Overexpression of OIP5-AS1 in neurons inhibits neuronal apoptosis induced by cerebral ischemia-reperfusion injury (CIRI) and exerts a neuroprotective role. Mechanistically, OIP5-AS1 may play a neuroprotective role after CIRI by up-regulating the expression of TAK1 binding protein 2 (TAB-2), reducing neuronal mitochondrial damage, and inhibiting apoptosis. OIP5-AS1 may become a novel therapeutic target for ischemic stroke.

Senkyunolide A attenuates cerebral ischemia-reperfusion injury by inhibiting NLRP3-mediated ferroptosis in PC12 cells.

Cerebral ischemia-reperfusion (I/R) is a serious complication in patients with ischemic stroke. Senkyunolide A (SenA) can alleviate neuronal cell damage induced by cerebral I/R; however, the exact action mechanism remains unclear. An in vitro cellular injury model was established by inducing PC-12 cells with OGD/R. The viability of SenA-treated PC-12 cells with or without OGD/R induction was detected with CCK-8 assay while the cell apoptosis was detected using TUNEL. The secretion of inflammatory cytokines, the activity of ROS, mitochondrial membrane potential and mtROS level were measured with ELISA, ROS assay kits, JC-1 staining and MitoSOX Red assay, respectively. The level of Fe2+ was detected with Fe2+ assay kits and lipid peroxidation was detected with TBARS assay. The expressions of lipid peroxides were measured using corresponding assay kits. Western blot was used to measure the expressions of NLRP3, apoptosis-, and ferroptosis-related proteins. The transfection efficiency of OV-NLRP3 was also detected using Western blot. The present study showed that SenA could attenuate viability damage, inflammatory response, oxidative stress, apoptosis and ferroptosis in OGD/R-induced PC-12 cells and it was identified that the cytoprotective effects of SenA on PC-12 cells stimulated by OGD/R may be associated with the inhibition of NLPR3. Collectively, SenA protects neuronal cells against cerebral I/R injury through the inhibition of NLRP3-mediated ferroptosis.

Patulin induced neuronal cell damage in human neuroblastoma SH-SY5Y Cells

Patulin induced neuronal cell damage in human neuroblastoma SH-SY5Y Cells

The neuroprotective effect of human umbilical cord MSCs-derived secretome against α-synuclein aggregates on the blood-brain barrier.

The blood-brain barrier (BBB) is a specialized network that maintains central nervous system homeostasis. Disruption of the BBB can lead to neuronal damage and contribute to neurodegenerative diseases like Parkinson's disease (PD), characterized by alpha-synuclein (αSN) aggregation, which forms intracellular inclusions. Mesenchymal stem cells (MSCs) have shown promise in alleviating the severity of neurological diseases through their paracrine secretions. However, the impact of MSCs secretome on the BBB remains largely unclear. In this study, we investigated the effect of human umbilical cord-derived MSCs (hUC-MSCs) secretome on the BBB in the presence of toxic αSN-aggregates (αSN-AGs). Using in vitro BBB models established through mono- and co-culture systems of hCMEC/D3 cells, we assessed the influence of the secretome on the cytotoxicity and inflammatory responses induced by αSN-AGs. Our results demonstrate that the hUC-MSCs secretome exerts protective effects by mitigating the toxic effects of αSN-AGs on the BBB. Specifically, this study shows a notable reduction in cytotoxicity and inflammation. Our findings highlight the potential of hUC-MSCs secretome as a promising candidate for innovative, cell-free therapies in PD treatment. Furthermore, we propose an optimized method for isolating MSCs from umbilical cord tissue, aimed at facilitating future research on the therapeutic applications of these cells.

S100A4 Exerts Neuroprotective Effects by Attenuating Blood-Brain Barrier Disruption and Oxidative Stress via the PI3K/Akt/Nrf2 Axis in Ischemic Stroke

Ischemic stroke is a major cause of disability and mortality worldwide, with oxidative stress and blood-brain barrier (BBB) injury playing crucial roles in its pathogenesis. Our RNA sequencing results revealed that S100 calcium-binding protein A4 (S100A4) is highly expressed in the middle cerebral artery occlusion (MCAO) mouse model. We analyzed S100A4 expression in ischemic stroke patients and in mice subjected to the MCAO model. Moreover, using adeno-associated virus (AAV)-mediated knockdown of S100A4 in mice, we evaluated its effects on neurological deficits, BBB integrity, and oxidative stress in MCAO mice. Bioinformatic analyses explored the potential downstream pathways of S100A4.S100A4 expression was significantly elevated in the serum of ischemic stroke patients and brain tissues of MCAO mice. AAV-mediated knockdown of S100A4 exacerbated neurological deficits, BBB disruption, and oxidative stress in MCAO mice. The upregulation of S100A4 mitigated these outcomes, which were facilitated through the stimulation of the PI3K/Akt/Nrf2 signaling cascade.Our results illustrate that S100A4 plays a protective role in preventing neuronal damage during ischemic stroke by reducing oxidative stress and preserving BBB integrity through the PI3K/Akt/Nrf2 pathway. This highlights its promise as a potential therapeutic approach for ischemic stroke.

The novel miR_146-Tfdp2 axis antagonizes METH induced neuron apoptosis and cell cycle abnormalities in tree shrew.

Methamphetamine (METH) is a synthetic drug with potent addictive, relapse, and neurotoxic properties. METH abuse contributes to severe damage to the central nervous system, potentially causing cognitive impairments, behavioral changes, and neurodegenerative diseases. METH-induced neuronal damage is closely related to apoptosis and cell cycle abnormalities, while gene expression regulator microRNAs (miRNAs) may play extensive roles in this progress, but the specific mechanisms remain unclear. We found that the novel miRNA 146 (miR_146) was downregulated in METH-induced apoptosis and cell cycle arrest in tree shrew primary neurons, while the expression of its target gene Tfdp2 was increased after METH exposure. Overexpression of miR_146 or silencing of Tfdp2 significantly alleviated METH-induced cell cycle arrest and apoptosis in primary tree shrew neurons. These findings provide new insights into the role of the miR_146-Tfdp2 axis in METH-induced neurotoxic injury and offer a theoretical basis for miR_146 as potential therapeutic targets in drug abuse.

Role of Gut-Microbiome-Brain-Axis in Neurodegenerative Diseases: A Review on Mechanisms and Potential Therapeutics

Neurodegenerative diseases encompass a group of disorders with diverse etiologies characterized by the accumulation of neurotoxic substances that contribute to neuronal damage and brain degeneration. The integration of the microbiota-intestine-brain axis mechanism occurs via afferent and efferent pathways with the assistance of the vagus nerve and peripheral circulation. The gut microbiota produces pathogenic proteins and other harmful substances that can cross the blood-brain barrier and develop into even more pathogenic proteins when in contact with the bloodstream. The microbial metabolites most commonly associated with neurodegenerative diseases are butyrate and amyloid, although the precise role and mechanism of their relationship with the microbiota have yet to be fully elucidated. Additionally, in Parkinson's disease, the microbiome is directly linked to an increase in opportunistic pathogens, a decrease in beneficial anti-inflammatory species, and higher levels of carbohydrate metabolizers.

Best1 mitigates ER stress induced by the increased cellular microenvironment stiffness in epilepsy.

Changes in brain tissue stiffness are closely linked to the development and diseases of the nervous system. Endoplasmic reticulum (ER) stress plays a role in various pathological processes related to epilepsy. However, the relationship between stiffness changes, ER stress, and epilepsy remains unclear. This study aimed to investigate the impact of Best1 upregulation on alleviating ER stress and the underlying mechanism. Additionally, we proposed a protective strategy to prevent cell death resulting from ER stress in epilepsy. This study investigated the expression levels of ER stress-related proteins in epileptic tissues of varying stiffness. Atomic force microscopy revealed differences in stiffness across various lesion regions in patients with epilepsy. The expression levels of ECM and ER stress-related proteins were elevated in tissues with higher stiffness. Polypropionamide hydrogels were used to simulate extracellular matrix (ECM) with varying stiffness levels. Basal ER stress increased in the stiffer hydrogel substrates. Furthermore, the calcium-activated anion channel Bestrophin 1 (Best1) mitigated ER stress induced by both the stiffer substrate and thapsigargin. The loss-of-function mutations in Best1 inhibited this activity. The underlying mechanism involves the upregulation of the endosomal sorting complex required for the transport (ESCRT) components by Best1, which helps mitigate ER stress. These findings suggest that increased stiffness of the cellular microenvironment may contribute to neuronal death during epileptogenesis. Additionally, Best1 upregulation may serve as a protective strategy against excessive ER stress-induced neuronal damage in epilepsy.

Exercise therapy facilitates neural remodeling and functional recovery post-spinal cord injury via PKA/CREB signaling pathway modulation in rats.

Neuronal structure is disrupted after spinal cord injury (SCI), causing functional impairment. The effectiveness of exercise therapy (ET) in clinical settings for nerve remodeling post-SCI and its underlying mechanisms remain unclear. This study aims to explore the effects and related mechanisms of ET on nerve remodeling in SCI rats. We randomly assigned rats to various groups: sham-operated group, sham-operated + ET, SCI alone, SCI + H89, SCI + ET, and SCI + ET + H89. Techniques including motor-evoked potential (MEP), video capture and analysis, the Basso-Beattie-Bresnahan (BBB) scale, western blotting, transmission electron microscopy, hematoxylin and eosin staining, Nissl staining, glycine silver staining, immunofluorescence, and Golgi staining were utilized to assess signal conduction capabilities, neurological deficits, hindlimb performance, protein expression levels, neuron ultrastructure, and tissue morphology. H89-an inhibitor that targets the protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway-was employed to investigate molecular mechanisms. This study found that ET can reduce neuronal damage in rats with SCI, protect residual tissue, promote the remodeling of motor neurons, neurofilaments, dendrites/axons, synapses, and myelin sheaths, reorganize neural circuits, and promote motor function recovery. In terms of mechanism, ET mainly works by mediating the PKA/CREB signaling pathway in neurons. Our findings indicated that: (1) ET counteracted the H89-induced suppression of the PKA/CREB signaling pathway following SCI; (2) ET significantly alleviated neuronal injury and improved motor dysfunction; (3) ET facilitated neuronal regeneration by mediating the PKA/CREB signaling pathway; (4) ET enhanced synaptic and dendritic spine plasticity, as well as myelin sheath remodeling, post-SCI through the PKA/CREB signaling pathway.

Neuroprotective potential of isofraxidin: Alleviating parkinsonian symptoms, inflammation and microglial activation.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Previous research has confirmed that isofraxidin can reduce macrophage expression and inhibit peripheral inflammation. However, its effects on the central nervous system remain underexplored. This study aims to determine whether isofraxidin offers protective effects against PD. To assess the effects of isofraxidin, motor performance changes in LPS-induced PD mice were evaluated using rotarod, pole-climbing, and beam-walking tests. Striatal damage was examined through [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) imaging, and dopaminergic neurotoxicity was assessed using tyrosine hydroxylase (TH) staining. Microglial accumulation and activation were monitored with Iba-1 staining, while LPS-induced inflammation was examined via TNF-α and IL-1β staining. Isofraxidin pre-treatment significantly improved LPS-induced motor dysfunction, as evidenced by better performance in the rotarod, pole-climbing, and beam-walking tests. [18F]FDG PET imaging showed that isofraxidin restored glucose uptake in the striatum, countering LPS-induced damage. Furthermore, Iba-1 staining revealed that isofraxidin markedly inhibited LPS-induced microglial activation and accumulation. TNF-α and IL-1β staining indicated a reduction in inflammation with isofraxidin treatment. Additionally, TH staining supported the neuroprotective role of isofraxidin on dopaminergic neurons. Isofraxidin exhibits notable neuroprotective properties by mitigating LPS-induced parkinsonian behaviors, microglial activation, inflammation, and dopaminergic neuron damage. These results highlight isofraxidin's potential as a therapeutic intervention for PD.

Hydrogen restores central tryptophan and metabolite levels and maintains mitochondrial homeostasis to protect rats from chronic mild unpredictable stress damage.

The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%-4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model. A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment. Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin. The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.

Corticosterone-induced postpartum depression induces depression-like behavior and impairs hippocampal neurogenesis in adolescent offspring via HPA axis and BDNF-mTOR pathway.

Postpartum depression (PPD) adversely affects the growth and development of the offspring, increasing the risk of various internalizing behaviorsduring adolescence. Studies have shown that corticosterone (CORT)-induced PPD affects neurogenesis in the offspring, which is closely related to the onset of depression. However, the underlying mechanisms of these changes in the offspring of PPD mothers remain unexplored. In this study, we demonstrated postpartum mice treated with high CORT experienced activation of the hypothalamic-pituitary-adrenal (HPA) axis, which induced depressive-like behavior and impaired maternal caring behavior. Furthermore, adolescent offspring of PPD mice exhibited depression-like behavior, and learning and memory deficits. These offspring also showed diminished levels of DCX+, decreased levels of synaptic proteins, and reduced dendritic spine density and length in hippocampus. Additionally, we detected increased serum stressed hormones and decreased hippocampal glucocorticoid receptor (GR) protein level in the offspring. We also found the offspring exhibited reduced expression of brain-derived neurotrophic factor (BDNF) and the phosphorylation tyrosine kinase receptor B (TrkB), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins in hippocampus. These results indicated that the behavioral deficits and neuronal damage observed in the offspring of PPD mice may be related to HPA axis dysfunction and inhibition of the BDNF-mTOR pathway. In conclusion, our findings confirm that CORT induces depression-like behavior and impairs maternal caring behavior in maternal mice, which in turn affects their offspring's emotion and cognitive behavior. This impact is characterized by the activation of the HPA axis and inhibition of the BDNF-mTOR pathway.

The Role of Microglia in Parkinson's Disease and Possible Therapeutic Targets

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to significant motor and non-motor symptoms. Recent research highlights the critical role of microglia, the resident immune cells of the central nervous system, in the pathogenesis and progression of PD. Microglia contribute to neuroinflammation through the release of pro-inflammatory cytokines and reactive oxygen species, exacerbating neuronal damage. Moreover, α-synuclein aggregates, a hallmark of PD, activate microglia, further promoting inflammation and neurodegeneration. This review explores the dual role of microglia in PD, encompassing both their neuroprotective functions and their contribution to neuroinflammation. We discuss the molecular mechanisms underlying microglial activation and their interactions with astrocytes, another crucial glial cell type. The review also examines potential therapeutic targets aimed at modulating microglial activity to mitigate neuroinflammation and slow the progression of PD. Current therapeutic strategies predominantly focus on symptomatic relief through dopaminergic medications. However, emerging therapies targeting microglial activation, such as anti-inflammatory drugs, immunomodulators, and novel agents like metabotropic glutamate receptor 5 (mGluR5) modulators, offer promising avenues for disease modification. Understanding the complex interplay between microglia and other cellular components in the PD brain is essential for developing effective treatments that address the underlying pathophysiological mechanisms of the disease.

Correlation Between Indoxyl Sulfate in Chronic Kidney Disease and Olfactory Dysfunction.

Olfactory dysfunction is prevalent among individuals with chronic kidney disease (CKD), with prevalence escalating alongside disease severity. The uremic toxin we observed in this study is Indoxyl sulfate (IS), a potent uremic toxin that markedly accumulates in the plasma of patients with chronic insufficiency. Olfactory damage may occur in the setting of neuronal damage due to renal failure. 27 patients, a total sample in this study with diagnosed chronic kidney disease within stage 5 on regular hemodialysis, were examined for indoxyl sulfate levels in blood plasma and then examined for their olfactory function using the Sniffin' Sticks test. A correlation analysis was conducted between indoxyl sulfate levels and olfactory function test results in patients with CKD. The Pearson correlation test revealed a strong, significant negative correlation between indoxyl sulfate levels and olfactory function (r = -0.613; p = 0.001). Additionally, correlations were found between indoxyl sulfate levels and each component of olfactory function: threshold value (r = -0.408; p = 0.035), discrimination (r = -0.807; p = 0.001), and identification (r = -0.703; p = 0.001). Olfactory function is compromised in individuals with chronic renal disease and correlates with the level of accumulation of the uremic toxin indoxyl sulfate.

CBL/Cbl-b mediates Fas degradation to reduce neuronal damage in experimental autoimmune encephalomyelitis.

Fas has been shown to positively regulate the differentiation of T helper 17 (Th17) cells in mouse models of experimental autoimmune encephalomyelitis (EAE). Fas protein expression is regulated by ubiquitination but has not been further studied. In this study, we investigated the role of the Fas ubiquitin ligase in Th17 cell differentiation and highlighted its potential as a therapeutic target for EAE. The E3 ubiquitin ligase CBL of Fas was predicted using the online prediction software ubibrowser. Overexpression of CBL significantly reduced Fas protein levels but did not affect mRNA levels. The decrease in Fas protein mediated by CBL overexpression was rescued by the proteasome inhibitor MG132. Co-IP analysis revealed that CBL interacted with Fas. Further results suggested that CBL regulated Fas expression through ubiquitination, thereby affecting Th17 cell differentiation. Cbl-b, a homologue of CBL, significantly promoted the degradation of Fas protein and increased its ubiquitination modification. Furthermore, CBL and Cbl-b could synergistically regulate Fas to influence Th17 cell differentiation. The same conclusion was also reached in animal models. Luxol Fast Blue staining showed that myelinated fibres in the spinal cord were significantly increased after CBL/Cbl-b overexpression in EAE. Finally, flow cytometry and immunofluorescence staining showed that overexpression of CBL or Cbl-b decreased the proportion of Th17 cells in the spinal cord of EAE mice, ultimately reducing neuronal damage. Taken together, these data demonstrate that CBL and Cbl-b can synergistically regulate Fas to inhibit Th17 cell differentiation, thereby alleviating spinal cord nerve injury in the EAE model.

Co-administration of coenzyme Q10 and curcumin mitigates cognitive deficits and exerts neuroprotective effects in aluminum chloride-induced Alzheimer's disease in aged mice.

Aluminum chloride (AlCl3), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays a pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes and efficacy of CoQ10 and curcumin low dose (100mg/kg each) combination in 18-months old geriatric male Balb/c mice subjected to AlCl3-prompted memory derangements (200mg/kg in water bottles) for 28days. The neuroprotective properties driven by antioxidant mechanisms were assessed via observing cellular pathology in key-memory related brain regions including the cornuammonis (CA3 and DG) and cortex 2/3 layer. Our outcomes revealed that AlCl3 exposure significantly reduced spatial learning and memory. In contrast, CoQ10 and curcumin combinatorial regime markedly mitigated cognitive deficits Vs. individual high-dose in AlCl3-treated animals as demonstrated by their improved performance in neurobehavioral tests such as the Y-maze, novel object recognition, passive avoidance and Morris-water maze test. Additionally, CoQ10 and curcumin co-administration restored redox balance by significantly reducing the levels of oxidative stressor (MDA) and increasing the anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved in acetylcholine breakdown which negatively impacts acetylcholine levels and memory function. AlCl3 exposure elevated AchE levels in mice brains vs. treatment. This neurochemical alteration was notably reversed in the dual-treatment group. Furthermore, CoQ10 and curcumin ameliorated AlCl3-induced neurotoxicity by preserving neuronal cytoarchitecture in both cortical and hippocampal regions. In conclusion, CoQ10 and curcumin combination might attenuate memory loss induced by AlCl3-intoxication via restoring aberrant AchE activity, enhanced anti-oxidant defenses and salvaging the deleterious neuronal damage.

IGF2BP2 Regulates the Progression of Alzheimer's Disease Through m6A-Mediated NLRP3 Inflammasome.

Recent studies show that N6-methyladenosine (m6A) plays an important role in the pathogenesis of the Alzheimer's disease (AD), while the mechanisms involved were studied insufficiently. The present study aimed to explore the effect of human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2), one of the m6A-binding proteins on the progression of AD. The mRNA and protein expression level were determined using RT-qPCR and western blot, respectively. MTT assay was carried out to evaluate cell viability. The content of ROS, antioxidant enzymes, IL-1β and pyroptosis, as well as m6A contents were determined using relative commercial kit. The AD models were built using Aβ1-42 -stimulated hippocampal neuron in vitro and AD mice in vivo. Our results showed that IGF2BP2 was significantly upregulated in the Aβ1-42 -stimulated hippocampal neuron. IGF2BP2 inhibition reversed the decreased cell viability and the increased cell apoptosis induced by Aβ1-42. IGF2BP2 siRNA transfection alleviated Aβ1-42 induced pyroptosis and pyroptosis-related proteins upregulation. we also found that IGF2BP2 inhibition downregulated the expression of NLRP3 through m6A methylation. Furthermore, overexpression of NLRP3 partly reversed the effect of IGF2BP2 inhibition on Aβ1-42 -induced hippocampal neuron injury. In addition, IGF2BP2 improved cognitive function and alleviated Aβ1-42 neuronal injury in vivo. Knockdown of IGF2BP2 inhibit neuronal damage and pyroptosis in the hippocampus cells, and improve cognitive function in AD partly through m6A-mediated NLRP3 inflammasome.