Peripheral metabolic disorders, which drive brain insulin resistance, increase the risk of cognitive impairment, a key contributor to Alzheimer's disease. Conditioned media derived from human mesenchymal stem cells (CM-hMSCs) have shown potential for modulating neurological pathways. Male and female offspring exposed to maternal and post-weaning high-fat diet (HFD) were treated with CM-hMSCs. Spatial memory and anxiety-like behaviors were assessed along with hippocampal markers of glucose metabolism, inflammation, and Alzheimer's disease-related pathways. In male offspring, CM-hMSCs partially improved molecular pathways involved in brain glucose metabolism, as indicated by increased hippocampal mRNA expression of Glut1, Glut4, and IDE, and elevated BDNF levels. CM-hMSC treatment also modulated the inflammatory profile, with increased IL-10 and reduced IL-1β in the hippocampus. However, CM-hMSCs did not produce significant improvements in behavioral outcomes. CM-hMSCs exert early, region-specific molecular effects on hippocampal glucose metabolism and inflammatory responses in HFD-exposed male offspring.

Dysfunction of neuronal networks such as aberrant excitability and disrupted oscillatory activity, especially within theta and gamma bands, in memory-related areas including the hippocampus and prefrontal cortex, is increasingly recognized as an important contributor to cognitive impairment in Alzheimer's disease (AD). In this context, targeting network dysfunction via gamma sensory entrainment, such as 40 Hz auditory stimulation, has emerged as a promising non-invasive therapeutic approach; however, the therapeutic mechanisms by which 40 Hz auditory stimulation ameliorates network-level deficits remain poorly understood. We studied the effects of long-term 40 Hz auditory stimulation in STZ-induced AD rats on the hippocampal-prefrontal network activity. Daily auditory stimulation was applied for 21 days, and its impact was assessed using electrophysiological recordings, behavioral testing, histological staining, and molecular analyses. STZ-treated rats exhibited impaired theta-gamma coupling, reduced hippocampal-prefrontal theta coherence, increased interictal epileptiform discharges, and significant deficits in spatial memory. These network abnormalities were associated with Aβ accumulation, tau hyperphosphorylation, altered expression of insulin/PI3K/Akt pathway-associated genes, and reduced expression of neurogenesis-related markers. Remarkably, 40 Hz auditory stimulation reversed many of these impairments: it restored functional connectivity and cross-frequency coupling, reduced epileptiform activity, improved memory performance, attenuated Aβ and tau pathology, partially normalized insulin/PI3K/Akt pathway-associated gene expression, and upregulated genes related to adult neurogenesis. Our findings indicated that 40 Hz auditory stimulation can effectively target both neural circuit dysfunction and molecular markers of AD, highlighting its potential as a simple, accessible, and multifaceted therapeutic strategy.

Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 ¹⁰ CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.

Introduction: Methamphetamine (MA) induces cell death through several mechanisms. Insulin has an important role in cell proliferation and apoptosis via GSK3 beta inactivation. Here, we evaluated the effect of insulin and SB-216763, a selective GSK3 beta inhibitor, on MA-induced cell death in neuroblastoma SH-SY5Y, and rat primary midbrain cells. Methods: Human SH-SY5Y and rat primary midbrain cells extracted from E14.5 rat embryo were treated with insulin (0.005-0.15U) or SB-216763 (0.5-9 mu M) with or without MA (5mM). The cell viabil-ity was assessed after 24, 48, and 72 h. TNF alpha, Bax, Bim, and Bcl2 genes expression were exam-ined in primary midbrain cells after 72 h of treatment with 5mM MA, insulin (0.05U), and SB-216763 (3 mu M). Results: MA significantly decreased the viability of human SH-SY5Y and rat primary midbrain cells, and insulin and SB-216763 could increase it. In addition, elevated expression of TNF alpha and Bax fol-lowing MA was attenuated by insulin and SB-216763 in primary midbrain cells. Conclusion: These findings demonstrated that MA decreases the cell viability of rat primary midbrain cells, at least in part, by upregulation of inflammatory and apoptotic factors, and treatment with insulin and SB-216763 could attenuate MA toxicity.

Alzheimer's disease (AD) presents an increasing global health challenge, highlighting the need for early and accessible diagnostic methods. This study introduces a highly sensitive optical fiber apta-biosensor based on localized surface plasmon resonance (LSPR) for the early detection of Amyloid beta (1-42) (A beta(42)), a crucial biomarker for AD. The RI sensitivity of the sensor was obtained at 716.53 nm/RIU which can be used as a good candidate for label-free biosensing. Upon A beta(42) binding, a distinct blue shift was observed, with a detection limit of 0.01 fM and a detection range from 50 fM to 5 mu M. The sensor's high sensitivity, real-time monitoring, and label-free operation highlight its potential as a cost-effective alternative for early AD diagnosis, paving the way for widespread clinical applications.

Alzheimer’s disease (AD), often described as “type 3 diabetes” due to its metabolic and neuroendocrine features, is marked by impaired glucose metabolism and insulin signaling. This study aimed to investigate whether regorafenib, a multi-kinase inhibitor, could modulate glucose metabolism, insulin/glucagon-like peptide-1 (GLP-1) pathways, and tau pathology in a streptozotocin (STZ)-induced rat model of AD. Male rats (n = 5–8/group) received intracerebroventricular STZ to induce AD-like pathology and were subsequently treated with regorafenib for two weeks. Cognitive function was assessed using the Y-maze and novel object recognition (NOR) tests. Glucose metabolism was evaluated via 18F-FDG micro-PET imaging and glucose tolerance tests. Serum and hippocampal markers of insulin, GLP-1, and tau phosphorylation were measured. Regorafenib-treated rats exhibited significant improvement in recognition memory in the NOR test, while enhancement in spatial working memory in the Y-maze did not reach statistical significance. Regorafenib improved glucose metabolism in both the brain and periphery, as demonstrated by imaging and tolerance testing. Treatment significantly increased serum insulin and GLP-1 levels, and reduced hippocampal hyperphosphorylated tau, although hippocampal gene expression of insulin and GLP-1 signaling pathways remained unchanged. Regorafenib may provide neuroprotective benefits in AD by improving glucose metabolism and reducing tau pathology. These findings suggest regorafenib as a potential novel therapeutic strategy for AD, though further research is needed to confirm its efficacy, assess long-term outcomes, and elucidate underlying mechanisms.

Introduction:Philosophy for Children (P4C) is one of the most effective teaching methods, having various educational, cognitive, and emotional benefits for children. This method is based on three types of thinking: critical (logic), caring (ethics), and creative (aesthetics). This study aimed to review the various outcomes of applying this strategy in people with different genders, ages, and socioeconomic statuses (SESs) from a neuroscience perspective. Methods:This is a narrative review study. The related studies were selected for review based on relevance to gender, age, and SES, and findings were categorized to highlight patterns and divergences in outcomes. Results:Evidence suggests that gender and SES can affect the effectiveness of P4C in certain aspects. However, the interaction between gender, age, and SES seems to shape the overall efficacy of P4C in nuanced ways. Conclusion:The P4C has shown promising benefits for diverse populations. However, demographic variables such as gender, age, and SES may modulate its impact. Further interdisciplinary research is needed to clarify these interactions and optimize implementation strategies.

Aging is commonly associated with cognitive decline, particularly in memory, and is linked to neuronal hyperexcitability and disrupted sleep-related oscillations in key brain regions such as the hippocampus and prefrontal cortex. Melatonin has been proposed as a potential therapeutic agent to counteract age-related cognitive impairments. In this study, 24-month-old male Wistar rats were treated with melatonin (10 mg/kg, intraperitoneally) for 30 days. Local field potentials were recorded from the hippocampus and prefrontal cortex to assess neuronal activity. Memory performance was evaluated using the novel object recognition test, and qPCR measured expression levels of inflammatory and amyloidogenesis markers. Melatonin treatment significantly reduced neuronal hyperexcitability, enhanced delta and theta oscillations, and increased sleep spindle amplitude, which were associated with improved memory performance. Additionally, melatonin attenuated the expression of pro-inflammatory markers without affecting the expression of amyloidogenesis-related genes. These findings suggest that melatonin may enhance cognitive function in aging by modulating neuronal excitability, sleep oscillations, and neuroinflammatory processes.

Neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD) and Parkinson’s disease (PD) are growing global health concerns characterized by progressive cognitive and motor impairments. Recent studies have reported the role of gut microbiota and its interaction with the microbiome-gut-brain axis (MGBA) in these disorders. Dietary polyphenols possess antioxidant and antiinflammatory properties, which might modulate gut microbiota and attenuate the progression of these NDDs by acting on MGBA. This systematic review evaluates the effects of polyphenols on gut microbiota, their metabolites, and gut microbiota-related mechanisms in NDDs. Following PRISMA guidelines, a comprehensive literature search was conducted across Embase, PubMed, Scopus, and Google Scholar databases. Studies investigating the effects of polyphenols on gut microbial metabolites and composition in NDDs were reviewed. Data were extracted on study design, interventions, and outcomes, and quality was assessed using SYRCLE’s risk of bias tool. Twenty-six animal studies met the inclusion criteria. Polyphenols favored microbial beneficial changes, increased short-chain fatty acids (SCFAs), and reduced neuroinflammation by modulating inflammatory cytokine profiles (IL-1β, TNF-α, and IL-6 reduction). In NDD animal models, memory and motor functions were observed to have improved, likely due to reduced oxidative stress, as well as decreased amyloid accumulation and improved gut and brain integrity. The interventions enriched beneficial genera (Bacteroidetes, Bifidobacterium, Lactobacillus, Rikenellaceae, and Alloprevotella) and reduced detrimental groups (Helicobacter, Bacteroidaceae, Rikenella, and Prevotella). The evidence suggests polyphenols may influence the gut microbiota and, in turn, alleviate NDD symptoms. However, we need to confirm this in more studies, especially in human studies.

Despite the great body of research done on Alzheimer's disease, the underlying mechanisms have not been vividly investigated. To date, the accumulation of amyloid-beta plaques and tau tangles constitutes the hallmark of the disease; however, dysregulation of the mammalian target of rapamycin (mTOR) seems to be significantly involved in the pathogenesis of the disease as well. mTOR, as a serine–threonine protein kinase, was previously known for controlling many cellular functions such as cell size, autophagy, and metabolism. In this regard, mammalian target of rapamycin complex 1 (mTORC1) may leave anti-aging impacts by robustly inhibiting autophagy, a mechanism that inhibits the accumulation of damaged protein aggregate and dysfunctional organelles. Formation and aggregation of neurofibrillary tangles and amyloid-beta plaques seem to be significantly regulated by mTOR signaling. Understanding the underlying mechanisms and connection between mTOR signaling and AD may suggest conducting clinical trials assessing the efficacy of rapamycin, as an mTOR inhibitor drug, in managing AD or may help develop other medications. In this literature review, we aim to elaborate mTOR signaling network mainly in the brain, point to gaps of knowledge, and define how and in which ways mTOR signaling can be connected with AD pathogenesis and symptoms.

Frazao This paper introduces an innovative two-core fiber (TCF) optic sensor employing a Mach-Zehnder interferometer (MZI) to monitor the optogenetic response of light-sensitive human dental pulp stem cells (hDPSCs). The in-fiber MZI, formed using a segment of TCF optic, detects refractive index (RI) changes in the surrounding medium. The sensor utilizes the evanescent wave of one core as the sensing arm, necessitating a thin cladding achieved through one-sided chemical etching. This design allows the sensor to detect subtle alterations in the RI of the environment by observing displacements in the interference spectrum. The optogenetic stimulation of light-sensitive cells induces variations in ion concentrations, leading to a corresponding change in refractive index. The fabricated sensor, with a peak sensitivity of 675.74 nm/RIU within the RI range of 1.39-1.43, can detect these changes. A computer simulation validated the sensitivity and optimized fabrication parameters, exhibiting satisfactory agreement with experimental results. Spectrum displacements were recorded for both light-sensitive hDPSCs and regular hDPSCs (as a control test). Results from the experiment, analyzed and compared using data analysis software, revealed that 473 nm blue light effectively stimulated light-sensitive hDPSCs. Notably, the proposed sensor, a novel structure, demonstrated its capability to detect RI changes in the cell medium during optogenetic applications.

Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.

Gut brain axis can affect the incidence of Alzheimer’s disease (AD). Probiotics restore the homeostasis of gut dysbiosis and prevent AD. Here, we evaluated the impact of Saccharomyces boulardii on rats with lipopolysaccharide (LPS)-induced amyloidogenesis. Rats were classified into four groups: (1) Control (saline), (2) LPS 250 µg/kg (saline + LPS), (3) S. boulardii (1010 CFU/mL/rat), and (4) S. boulardii (1010 CFU/mL/rat) + LPS (250 μg/kg). The passive behavioral test, Western blotting, and immunohistochemistry were done using the animal hippocampi. Step-through latency (STL) indicated that the LPS-treated group had decreased memory retrieval compared to the control group. The LPS group had increased hippocampal levels of amyloid-β peptide, amyloid-β precursor protein (APP), and β-secretase (BACE). Administration of the S. boulardii before LPS prolonged STL which has been shortened in the LPS group (P < 0.05). In the LPS + S group, S. boulardii reduced the levels of APP significantly compared to the LPS group (P < 0.01). S. boulardii mitigated Aβ buildup and memory dysfunction caused by LPS through modulating the APP, BACE1, and Aβ pathways. Future studies are required to explain the neuroprotective effects of S. boulardii, since it could be a novel therapy or prevention strategy for AD.

In recent years, glutamate has attracted significant attention for its roles in various brain processes. However, one of its key regulators, glutamate dehydrogenase (GDH), remains understudied despite its pivotal role in several biochemical pathways. Dysfunction or dysregulation of GDH has been implicated in aging and various neurological disorders, such as Alzheimer's disease and Parkinson's disease.In this review, the impact of GDH on aging, cognitive impairment, and neurodegenerative conditions, as exemplars of the phenomena that may affected by neuroplasticity, has been reviewed. Despite extensive research on synaptic plasticity, the precise influence of GDH on brain structure and function remains undiscovered. This review of existing literature on GDH and neuroplasticity reveals diverse and occasionally conflicting effects. Future research endeavors should aim to describe the precise mechanisms by which GDH influences neuroplasticity (eg. synaptic plasticity and neurogenesis), particularly in the context of human aging and disease progression. Studies on GDH activity have been limited by factors such as insufficient sample sizes and varying experimental conditions. Researchers should focus on investigating the molecular mechanisms by which GDH modulates neuroplasticity, utilizing various animal strains and species, ages, sexes, GDH isoforms, brain regions, and cell types. Understanding GDH's role in neuroplasticity may offer innovative therapeutic strategies for neurodegenerative and psychiatric diseases, potentially slowing the aging process and promoting brain regeneration.

The application of optical fibers in optogenetics is rapidly expanding due to their compactness, cost-effectiveness, sensitivity, and accuracy. This paper introduces a twin-core optical fiber (TCF) sensor employing a Mach-Zehnder interferometer (MZI) to monitor the optogenetic response of opsin-expressing human dental pulp stem cells (hDPSCs) based on refractive index (RI) measuring. In order to improve the RI sensitivity of the sensor, an in fiber Mach-Zeander modulator formed using TCF optics segments can detect changes in the RI in the surrounding medium, and in order to improve the RI sensitivity of the sensor, it is proposed to etch one side of the TCF cladding. The RI sensitivity of the sensor was obtained 233.62 nm/RIU in the range of 1.33-1.4 RIU and 870.01 nm/RIU in the range of 1.4-1.43 RIU, R2 = 0.99. simulation results show that in terms of sensor sensitivity and spectral response, there is a good agreement between the theoretical and experimental results, indicating that the TCF-MZI sensor can perform optical neural recording. In vitro experiments monitored wavelength changes in opsin-expressing and non-opsin-expressing in human dental pulp stem cells (hDPSCs) during optogenetic stimulation with 473 nm pulsed illumination. The results revealed that optical stimulation of ChR2 opsin-expressing hDPSCs leads to active the light sensitive ion channel and changing the effective RI of the surrounding medium. The neural activity is driven by changes in intracellular and extracellular ion concentrations, which lead to alterations in the RI of the cell medium RI variations detectable by the sensor. The novel sensor structure demonstrated its ability to detect RI changes in the cell medium during optogenetic stimulation and fiber optic sensors can be a good candidate for optical recording of the neural activity. Beyond these in vivo applications, label free fiber optic biosensors-based IR measurement can be used for all optical multifunctional probe in stimulation, recording, and sensing of neuroscience applications.

Aims Alzheimer's disease is characterized by memory loss and pathological changes in the brain, such as amyloid beta and tau pathology, disruptions in neural circuits and neuronal oscillations are also significant indicators of this disease and potential therapeutic targets. We studied how intranasal insulin impacts memory and neural oscillations in an Alzheimer's disease rat model induced by STZ. Main methods Male Wistar rats were intracerebroventricularly injected with STZ, followed by intranasal insulin therapy. Electrophysiological recordings were conducted in the hippocampus and medial prefrontal cortex to assess local field potentials. Memory was assessed using novel object recognition and Y-maze tests. Amyloid and tau pathology and neuronal loss were also evaluated in the hippocampus. Key finding Alterations in theta-gamma oscillations following insulin treatment were not significant. However, insulin administration ameliorated hippocampal sharp-wave ripples deficit and augmented hippocampal-prefrontal theta coherence. Concurrently, insulin therapy enhanced spatial memory and object recognition memory performance in behavioral tests. Insulin mitigated tau and amyloid pathology and hippocampal neuronal loss. Significance Our findings underscore the potential of intranasal insulin to enhance memory function by modulating hippocampal-prefrontal cortical synchronization and alleviating impairments in hippocampal sharp-wave ripples.

Previous research have reported that modulating the gut microbiome composition by fecal microbiota transplantation and probiotic administration can alleviate seizure occurrence and severity. Saccharomyces boulardii (SB) is a yeast probiotic that has demonstrated ameliorating effects on anxiety, memory and cognitive deficit, and brain amyloidogenesis. In this research, our goal was to examine the anti-seizure effects of SB on the pentylenetetrazole (PTZ)-kindled male Wistar rats. The animals were randomly categorized into four test groups. The rats were orally administered with saline (control and PTZ groups) or S. boulardii (SB + PTZ and SB groups) for 57 days. From the 29th day of the experiment, the animals received intraperitoneally saline (control and SB groups) or PTZ (PTZ and SB + PTZ groups) on alternate days for 30 days. The administration dose of SB and PTZ was 1010 CFU/ml/day and 35 mg/kg, respectively. We assessed animal seizure behavior, neuroinflammation, oxidative stress, and the levels of matrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) in the hippocampus tissue. S. boulardii hindered the PTZ-induced kindling development. SB treatment elevated glutathione (GSH) and total antioxidant capacity (TAC) and reduced malondialdehyde (MDA) levels. SB also lessened the hippocampal levels of BDNF and MMP-9. Following SB supplementation, proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-6 were lowered, and anti-inflammatory cytokine IL-10 was enhanced. Overall, our data indicated, for the first time, the positive impact of SB on the PTZ-kindled seizure rat model. The anti-seizure activity of SB was mediated by modulating oxidative stress, neuroinflammation, and MMP-9 and BDNF levels.

Background and Objectives: Cholestasis can lead to oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and ultimately causes cognitive damage, such as memory malfunctions. Considering their anti-inflammatory and protective effects, nanoparticles may be effective for the treatment of neurological disorders or for transferring medications through the blood-brain barrier. This study investigated the protective effect of yttrium oxide nanoparticles (Y2O3NPs) on cognitive disorders, inflammatory response and mitochondrial biogenesis caused by cholestasis in rat hippocampus. Methods: Male Wistar rats were randomly divided into seven groups: control, sham, vehicle, cholestasis, and three groups of cholestatic rats, which received doses of 0.1, 0.3, and 0.5 mg/kg Y2O3NPs, respectively for 21 days. The Morris water maze, passive avoidance, and elevated plus maze tests were used to assess the learning and memory of the rats. The expression of genes involved in mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM) and pro-inflammatory genes (TNF-α, IL-6, and IL-1β) were evaluated by real-time PCR technique. Results: Cholestasis led to learning and memory dysfunctions, decreased the expression of genes involved in mitochondrial biogenesis, and increased the expression of genes involved in neuroinflammation. Intraperitoneal injection (IP) of Y2O3NPs, especially at a dose of 0.5 mg/kg, enhanced the recognition and recall memory, increased the expression of factors involved in mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), and decreased neuroinflammation (TNF-α, IL-6, and IL-1β). Conclusion: This study demonstrated that Y2O3NPs reduced memory disorders caused by cholestasis. This nanoparticle increased the expression of factors involved in mitochondrial biogenesis, reduced the inflammatory responses in the hippocampus of cholestasis animals, and possibly alleviated cognitive disorders through this mechanism.