Search Results (20,041)

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and chronic neuroinflammation. Increasing evidence suggests that the imbalance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T (Treg) cells plays a critical role in AD pathogenesis. However, a comprehensive synthesis of how natural compounds modulate Th17/Treg balance in AD remains lacking. This review aims to summarize current preclinical evidence on Th17/Treg dysregulation and evaluate the immunomodulatory potential of natural compounds in AD. Methods: This review focuses on preclinical evidence derived from experimental AD models and related inflammatory models to evaluate how natural compounds modulate Th17/Treg balance, neuroinflammation, and cognitive function, with an emphasis on underlying molecular and immunometabolic mechanisms. Results: Th17/Treg imbalance contributes significantly to AD-associated neuroinflammation and disease progression. Representative natural compounds, including paeoniflorin, quercetin, and ganoderic acid A, have demonstrated the ability to rebalance Th17/Treg responses, suppress neuroinflammation, and improve neuronal survival in experimental models. These compounds are highlighted due to their relatively stronger evidence in AD-related models and more clearly defined immunomodulatory mechanisms. These effects are partially mediated through modulation of key signaling pathways and immunometabolic reprogramming. Conclusions: Targeting Th17/Treg balance with natural compounds represents a promising multi-target immunomodulatory strategy for AD. However, most current evidence is derived from preclinical or non-AD models, and clinical validation remains limited. Future studies should prioritize AD-specific models and translational research to evaluate therapeutic potential in humans. Full article

Chondroitin sulfate (CS) chains are major components of the extra- and pericellular matrix in the central nervous system (CNS), and their sulfation patterns influence CNS development and function. Highly sulfated CS preparations, including CS-D- and CS-E-enriched forms, have been shown to facilitate neurite outgrowth in cultured mouse hippocampal neurons. Notably, neurons cultured on CS-D- or CS-E-enriched substrates exhibited the following distinct morphological characteristics: CS-D promoted the extension of multiple short neurites, whereas CS-E induced the formation of a single elongated neurite with a polarization-like morphology. These features are consistent with early stages of neuronal polarization. However, the specific roles of these highly sulfated CS forms in polarization-like morphology remain unclear. In this study, we demonstrate that polarization-like morphological transitions in hippocampal neurons can be modulated on mixed CS-D/CS-E substrates by varying their ratios. Compared with CS-D-enriched substrates, CS-E-enriched substrates more effectively promoted polarization-like neuronal morphology, accompanied by enhanced activation of Src-family kinases. Furthermore, forced activation of Fyn kinase induced morphological changes resembling polarization-like features in a neuroblastoma cell line, even in the absence of CS-D/CS-E mixed substrates. In conclusion, highly sulfated CS subtypes may function as extracellular cues that regulate neuronal morphology via Src-family signaling, with likely involvement of Fyn. Full article

A growing number of studies have highlighted the various sensory interactions involved in the musical experience, as relationships between music and dimensions of taste, olfaction, sound, and visual qualities, such as associations between pitch and the size of images or objects, spatial location and frequency, and instrumental timbres and visual shapes. These studies share the premise that the way we relate to the musical phenomenon, whether in the processes of production, perception, or understanding, emerges from an integrated and intrinsically multisensory perceptual event. Nevertheless, because music is present daily in everyday life and because this experience is inherently subjective, such interactions tend to occur so naturally and seem so obvious that they have been relegated to common sense. On the other hand, evidence indicates that sensory interactions constitute a fundamental ancestral mechanism for cognitive and neuronal development governed by non-arbitrary tendencies, multiple variables, and patterns of predictability. The novel contribution of this review is to advance a dynamic theoretical model of multisensory musical experience that takes crossmodal correspondences as its central organising axis, articulated through three structuring principles (universality, congruence effect, hierarchical tendency) and their interaction with musical organisation, cognitive structure, and the sensory systems mobilised by music. A future research agenda is also proposed to broaden and deepen investigations in the field of music psychology and human development. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid β accumulation, tau pathology, chronic neuroinflammation, and metabolic stress converge to drive synaptic dysfunction and neuronal loss. Rather than resulting from a single mechanism, increasing evidence indicates that neurodegeneration in AD is mediated by the coordinated activation of multiple regulated cell death pathways. These pathways include apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, each characterized by distinct molecular mediators and execution programs. Evidence from human brain tissues, animal models, and in vitro systems demonstrates that core pathological drivers such as amyloid β and tau pathology, oxidative stress, and sustained neuroinflammation engage these death pathways in a spatially, temporally, and cell-type-dependent manner across neurons and glial populations. In this review, we synthesize the current knowledge on regulated cell death mechanisms in AD, emphasizing their molecular signatures, cellular specificity, and stage-dependent involvement, together with recent advances in immunohistochemical, imaging, and biofluid-based approaches for detecting neuronal death. By integrating evidence across molecular, cellular, and system levels, this review positions regulated cell death as a unifying framework for understanding neurodegeneration and developing pathway-specific biomarkers and combinatorial neuroprotective strategies. Full article

In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as “aerobic glycolysis”. Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, “The Astrocyte Neuron Lactate Shuttle Hypothesis” and “The Efficiency Tradeoff Hypothesis,” respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate. Full article

Migraine is a highly prevalent and disabling neurovascular disorder that represents a major global health burden due to its significant impact on quality of life and socioeconomic costs. Increasing evidence suggests that migraine pathophysiology involves complex interactions between neuronal hyperexcitability, vascular dysregulation, oxidative stress, and neuroinflammatory processes. Oxidative and nitrosative stress are increasingly recognized as key contributors to migraine mechanisms, influencing mitochondrial dysfunction, cortical spreading depression, and trigeminovascular activation. Nitric oxide plays a central role in these processes by regulating vascular tone, nociceptive signaling, and neurogenic inflammation through downstream pathways such as the soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling cascade. Dysregulation of nitric oxide signaling and increased oxidative stress may contribute to endothelial dysfunction and impaired cerebrovascular regulation observed in migraine patients. In addition, accumulating evidence highlights the role of neuroinflammatory mechanisms, including microglial activation and cytokine-mediated signaling, which may amplify nociceptive transmission within trigeminal pathways. Migraine is increasingly recognized as a systemic disorder associated with several comorbid conditions, including Parkinson’s disease, fibromyalgia, and autoimmune diseases such as Sjögren’s syndrome. This review summarizes recent advances regarding the interactions between oxidative stress, nitric oxide signaling, endothelial dysfunction, and neuroinflammation in migraine and discusses their potential therapeutic implications. Full article

Neurovascular coupling (NVC) maintains appropriate cerebral blood flow (CBF) in response to neuronal activity, and its disturbance, known as neurovascular uncoupling (NVU), is increasingly recognised as a major contributor to neurodegenerative disease. Alzheimer’s disease (AD) NVU is caused by Aβ buildup, tau pathology, endothelial dysfunction, and persistent neuroinflammation, leading to poor CBF control and blood–brain barrier (BBB) disintegration. Parkinson’s disease (PD) is characterised by α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and dopaminergic neuronal loss, all of which impede cerebrovascular regulation. These disease-specific mechanisms interact via similar vascular pathways, establishing NVU as a critical connection between neuronal degeneration and cerebrovascular dysfunction. This study highlights the critical role of NVU in neurodegeneration by investigating shared and disease-specific processes in AD and PD. Tau pathology disturbs vascular regulation in AD, whereas dopaminergic neuron loss impairs cerebrovascular control in PD. Both Aβ and α-synuclein are linked to endothelial dysfunction and oxidative stress, albeit originating in different pathologies. Comparative analysis reveals distinct vascular abnormalities in each condition, as well as shared processes such as inflammation and BBB disruption. The study also covers developments in biomarker discovery and neuroimaging techniques that allow for exact characterisation of NVU, facilitating early diagnosis and treatments. In addition, lifestyle changes and pharmacological treatments for oxidative stress and endothelial injury are being examined. This study highlights the significance of NVU as a fundamental pathogenic mechanism, underscoring its importance for comprehending disease development and formulating novel therapeutic strategies. Full article

Cadmium (Cd), a common environmental and occupational toxicant, is an important risk factor for neurodegenerative diseases. Metformin has been found to have neuroprotective effect, in addition to antidiabetic function. Our recent studies have identified that metformin ameliorates Cd neurotoxicity via blocking ROS-dependent PP5/AMPK-JNK signaling pathway. Here we further show that metformin protected PC12 cells and primary neurons from Cd-poisoning by mitigating Cd-induced increases in ATG5/LC3-II/p62 levels and autophagosomes. Knockdown of ATG5 dramatically potentiated the inhibitory effects of metformin on Cd-induced LC3-II, cleavage of caspase-3, accumulation of autophagosomes and apoptosis in PC12 cells. Addition of chloroquine (CQ) strengthened the basic and Cd-elevated ATG5/LC3-II/p62 levels, autophagosome accumulation and cell apoptosis, whereas metformin powerfully blocked the events, implying a metformin-promoted autophagic flux-dependent mechanism involved. Further research revealed that metformin prevented Cd-induced autophagic flux impairment and cell apoptosis, which was attributed to restraining Cd inactivation of AMPK. This is supported by the findings that activation of AMPK with AICAR or ectopic expression of constitutively active AMPKα (AMPKα-ca) reinforced the inhibitory effects of metformin on Cd-evoked ATG5/LC3-II/p62/autophagosomes and apoptosis in PC12 cells and/or primary neurons. Taken together, the results indicate that metformin protects neuronal cells from Cd-induced autophagic flux impairment-dependent apoptosis by activating AMPK. Our studies highlight that metformin has a great potential for prevention of Cd toxicity related to neurodegenerative diseases. Full article

Metabolic diseases are strongly associated with chronic systemic inflammation and oxidative stress, which disrupt the microbiota–gut–brain (MGB) axis and promote neuroinflammation. Dysbiosis favors the release of proinflammatory metabolites, reactive oxygen species (ROS), and lipopolysaccharides (LPS), increasing intestinal permeability and triggering systemic immune responses that reach the central nervous system (CNS) through a weakened blood–brain barrier (BBB). This review summarizes current knowledge on the pathophysiological mechanisms linking the MGB axis, metabolic disorders, and neuroinflammation, as well as the therapeutic potential of antioxidants. A literature search was conducted in PubMed, Web of Science, Scopus, and ScienceDirect and included original research articles, reviews, clinical trials, and meta-analyses related to microbiota, neuroinflammation, oxidative stress, and antioxidant interventions. Evidence indicates that dysbiosis exacerbates metabolic dysfunction by activating the nuclear factor kappa B (NF-κB) and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathways, while excessive ROS production impairs mitochondrial function, neuronal survival, and cognitive processes. Antioxidant strategies, including polyphenols, omega-3 fatty acids, curcumin, vitamins C and E, and probiotics, can restore microbial diversity, reinforce intestinal and BBB integrity, and modulate oxidative and inflammatory signaling. In conclusion, supplements and bacteria with antioxidant properties show promising therapeutic effects by targeting oxidative stress mechanisms involved in metabolic diseases and their pathological consequences, such as dysbiosis and neuroinflammation. Full article

The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson’s disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)—a naturally occurring thiol/thione derivative abundant in mushrooms—as a promising candidate, given its long half-life, blood–brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic. Full article

Titanium dioxide nanoparticles (TiO₂ NPs), widely used as food additives, frequently coexist with high-fat diets (HD) in modern dietary patterns, yet their combined in vivo toxicity remains poorly understood. This study investigated the multi-organ effects of co-exposure to TiO₂ NPs or food-grade E171 and HD in male C57BL/6J mice. Mice were randomly assigned to six groups and fed regular or high-fat diets containing 1 wt% TiO₂ NPs or E171 for 13 weeks. Histopathology, serum biochemistry, organ coefficients, and open-field behavioral tests were used to assess tissue injury and functional alterations. Co-exposure to TiO₂ NPs and HD markedly exacerbated tissue damage across multiple organs. In the liver, more severe ballooning degeneration, necrosis, and inflammatory infiltration were observed, accompanied by altered liver enzymes and reduced organ coefficients. Intestinal injury was characterized by crypt distortion and increased inflammation, particularly in the HD + TiO₂ group. Testicular tissues showed disorganized seminiferous tubules, loss of spermatogenic cells, and interstitial hyperplasia. In the brain, hippocampal neurons exhibited pyknosis and disarray, with decreased brain coefficients and impaired exploratory behavior. E171 induced similar but milder effects. These findings indicate that HD enhances TiO₂ NPs induced multi-organ toxicity, highlighting the health risks of realistic co-exposure to dietary nanoparticles and high-fat foods. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Glomeruli are signal-processing units of the olfactory bulb (OB) that play a key role in many OB computations, including contrast enhancement, gain control, and odorant-selective habituation. In awake mice, we unveil an extremely stable, inhomogeneous map of basal glomerulus-specific activity that serves as the background against which olfactory signal processing occurs. This activity is strongly driven by centrifugal cholinergic inputs; endogenous and airflow-evoked spiking of olfactory sensory neurons; and, to a minor extent, by the odor environment. Moreover, it is brain-state dependent and suppressed under various forms of anesthesia, and is therefore likely attenuated during sleep. These results reveal an important layer in the OB signal-processing network, likely increasing the system’s variance and dynamic range via glomerulus-specific functional inhomogeneity. Full article

Gabapentin is widely used for epilepsy and neuropathic pain. Beyond neurological indications, preclinical evidence suggests that gabapentin may exert anti-inflammatory effects that have not been systematically reviewed. A systematic review (2015–2025) was performed, resulting in thirteen in vitro and in vivo studies evaluating gabapentin’s impact on inflammatory signaling pathways, cytokine production, immune cell activity, and tissue inflammation. Outcomes included molecular pathways, inflammatory mediators, histopathological changes, and functional inflammatory measures. Risk of bias and study quality were assessed using the SYRCLE RoB tool for in vivo studies and the SciRAP approach for in vitro studies. Gabapentin demonstrated potential modulation of inflammatory responses in neuropathic pain, neuroinflammation, uveitis, and sepsis models through inhibition of MAPK and NF-κB signaling, reduction in pro-inflammatory cytokines, modulation of PPAR signaling pathways, and activation of Nrf2/HO-1 pathway. Gabapentin’s pharmacological actions extend beyond neuronal excitability to include modulation of inflammatory pathways, supporting a broader biological role for gabapentin. Although preclinical data support gabapentin’s potential anti-inflammatory properties, further targeted experimental and clinical studies are warranted to confirm these findings. Full article

Mitochondria are essential organelles that perform irreplaceable functions in neurons. The degeneration of neurons in Alzheimer’s disease (AD) is associated with mitochondrial damage, and Tau pathology represents a significant pathogenic factor in AD. However, the relationship between Tau and mitochondrial dysfunction during neuronal degeneration remains unclear. In this study, we investigated the effects and mechanisms by which extracellular Tau aggregates induce neuronal mitochondrial damage and dysfunction. The results showed that extracellular Tau aggregates lead to structural damage of mitochondria in SH-SY5Y cells and disrupt mitochondrial homeostasis. Extracellular Tau aggregates can also cause mitochondrial oxidative stress and inhibit oxidative phosphorylation in SH-SY5Y cells. Concurrently, extracellular Tau aggregates promote neuronal death through an increase in cytochrome C, mtDNA leakage and activation of the cGAS/STING pathway. We also explored the effects of a single-chain variable fragment antibody (scFv T1) and found that scFv T1 alleviated mitochondrial damage and dysfunction by inhibiting the formation of Tau aggregates. These findings suggest that targeting Tau pathology may be crucial to address neuronal mitochondrial impairment and that reduction of the toxicity associated with extracellular Tau aggregates could help slow Tau pathology progression. Full article