Search Results (378)

Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use. Full article

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management. Full article

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders. Full article

Neurodegenerative diseases (NDDs) such as Alzheimer’s, Parkinson’s, ALS, and Huntington’s pose a growing global challenge due to their complex pathobiology and aging demographics. Once considered as cellular debris, small extracellular vesicles (sEVs) are now recognized as active mediators of intercellular signaling in NDD progression. These nanovesicles (~30–150 nm), capable of crossing the blood–brain barrier, carry pathological proteins, RNAs, and lipids, facilitating the spread of toxic species like Aβ, tau, TDP-43, and α-synuclein. sEVs are increasingly recognized as valuable diagnostic tools, outperforming traditional CSF biomarkers in early detection and disease monitoring. On the therapeutic front, engineered sEVs offer a promising platform for CNS-targeted delivery of siRNAs, CRISPR tools, and neuroprotective agents, demonstrating efficacy in preclinical models. However, translational hurdles persist, including standardization, scalability, and regulatory alignment. Promising solutions are emerging, such as CRISPR-based barcoding, which enables high-resolution tracking of vesicle biodistribution; AI-guided analytics to enhance quality control; and coordinated regulatory efforts by the FDA, EMA, and ISEV aimed at unifying identity and purity criteria under forthcoming Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. This review critically examines the mechanistic roles, diagnostic potential, and therapeutic applications of sEVs in NDDs, and outlines key strategies for clinical translation. Full article

Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer’s disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS. Full article

A properly functioning capillary microcirculation is essential for sufficient oxygen and nutrient delivery to the central nervous system. The physical mechanisms governing the transport of red blood cells (RBCs) inside the narrow and irregularly shaped capillary lumen are complex, but understanding them is essential for identifying the root causes of neurological disorders like cerebral ischemia, Alzheimer’s disease, and other neurodegenerative conditions such as concussion and cognitive dysfunction in systemic inflammatory conditions. In this work, we conducted numerical simulations of three-dimensional capillary models, which were acquired ex vivo from a mouse retina, to characterize RBC transport. We show how the spatiotemporal velocity of the RBCs deviates in realistic capillaries and equivalent cylindrical tubes, as well as how this profile is affected by hematocrit and red cell distribution width (RDW). Our results show a previously unprecedented level of RBC velocity fluctuations in capillaries that depends on the geometric features of different confinement regions and a capillary circularity index $\left(I_{cc}\right)$ that represents luminal irregularity. This velocity fluctuation is aggravated by high hematocrit conditions, without any further effect on RDW. These results can provide a better understanding of the underlying mechanisms of pathologically high capillary transit time heterogeneity that results in microcirculatory dysfunction. Full article

Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, two significant factors in neurodegenerative diseases. This review examines the mechanisms by which metformin mitigates neuronal damage. Metformin reduces neuroinflammation by inhibiting microglial activation and suppressing proinflammatory cytokines. It also triggers the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway to combat oxidative stress, an essential regulator of antioxidant defenses. These outcomes support the possible neuroprotective roles of metformin in type 2 diabetes-related cognitive decline and conditions like Alzheimer’s disease. Metformin’s therapeutic potential is further supported by its capacity to strengthen the blood–brain barrier’s (BBB’s) integrity and increase autophagic flux. Metformin also offers several neuroprotective effects by targeting multiple pathological pathways. Moreover, metformin is being studied for its potential benefits beyond glycemic control, particularly in the areas of cognition, Alzheimer’s disease, aging, and stroke management. Evidence from both clinical and preclinical studies indicates a complex and multifaceted impact, with benefits varying among populations and depending on underlying disease conditions, making it an appealing candidate for managing several neurodegenerative diseases. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β plaque accumulation, tau tangles, and extensive neuroinflammation. Neuroinflammation, driven by glial cells like microglia and astrocytes, plays a critical role in AD progression. Initially, these cells provide protective functions, such as debris clearance and neurotrophic support. However, as AD progresses, chronic activation of these cells exacerbates inflammation, contributing to synaptic dysfunction, neuronal loss, and cognitive decline. Microglia release pro-inflammatory cytokines and reactive oxygen species (ROS), while astrocytes undergo reactive astrogliosis, further impairing neuronal health. This maladaptive response from glial cells significantly accelerates disease pathology. Current AD treatments primarily aim at symptomatic relief, with limited success in disease modification. While amyloid-targeting therapies like Aducanumab and Lecanemab show some promise, their efficacy remains limited. In this context, natural compounds have gained attention for their potential to modulate neuroinflammation and promote neuroprotection. Among these, butyrate and lauric acid are particularly notable. Butyrate, produced by a healthy gut microbiome, acts as a histone deacetylase (HDAC) inhibitor, reducing pro-inflammatory cytokines and supporting neuronal health. Lauric acid, on the other hand, enhances mitochondrial function, reduces oxidative stress, and modulates inflammatory pathways, thereby supporting glial and neuronal health. Both compounds have been shown to decrease amyloid-β deposition, reduce neuroinflammation, and promote neuroprotection in AD models. This review explores the mechanisms through which butyrate and lauric acid modulate glial and neuronal activity, highlighting their potential as therapeutic agents for mitigating neuroinflammation and slowing AD progression. Full article

Neuroinflammation is a key process in Alzheimer’s disease (AD). We aimed to examine the development and evaluation of a comprehensive in vitro model that captures the complex interplay between neurons and immune cell types. Retinoic acid-differentiated SH-SY5Y neuroblastoma cells exposed to LPS-conditioned media (CM) from RAW264.7 macrophages, BV2 microglia, and HL60 promyelocytic cells differentiated into neutrophil- or monocyte-like phenotypes were analyzed. The effects of CM containing inflammatory factors on neuronal viability and function were systematically evaluated. Neuronal oxidative stress, mitochondrial function, autophagy and protein aggregates were analyzed. The involvement of insulin resistance was studied by assaying glucose uptake and determining its IC₅₀ values for cell viability improvement and GSK3β phosphorylation. After short-term exposure (3 h), most inflammatory CMs induced peroxide production in neurons, with the strongest effect observed in media from DMSO- or RA-differentiated HL60 cells. Mitochondrial membrane potential was markedly reduced by LPS-stimulated BV2 and HL60-derived CMs. Prolonged exposure (72 h) revealed partial normalization of oxidative stress and mitochondrial membrane potential. Glucose uptake was significantly impaired in cells treated with LPS-activated RAW264.7, BV2, and DMSO-differentiated HL60 cell media, while insulin partially rescued this effect, except for the CM of BV2 cells. Notably, insulin IC₅₀ increased dramatically under LPS-treated BV2 cells induced inflammation (35 vs. 198 pM), confirming the development of insulin resistance. Immune cell-specific inflammation causes distinct effects on neuronal oxidative stress, mitochondrial function, protein aggregation, insulin signaling and viability. LPS-activated BV2-derived CM best recapitulates AD-related pathology, offering a relevant in vitro model for further studies. Full article

Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia. Full article

Determining the genetic variations of candidate genes in affected subjects will help identify early pathological biomarkers of Alzheimer’s disease (AD) and develop effective treatments. It has recently been found that some genes that are linked share an increase in intron retention (IR). In this review, we discuss a few instances of mRNA-IR in various genes linked to AD, including APOE, MAPT-Tau, Psen2, Farp1, Gpx4, Clu, HDAC4, Slc16a3, and App genes. These genes are vulnerable to IR, encompassing additional crucial proteins for brain functionality, but they are frequently involved in pathways linked to the control of mRNA and protein homeostasis. Despite the advancements in human in vivo RNA therapy, as far as we know, there are no reports of data generated regarding artificial in vivo splicing in either animal models or humans. To prevent genetic variations and improve or repair errors in expression of desired genes, humans have adopted new gene editing techniques like CRISPR-Cas9 and RNAi modalities. Ultimately, IR could be utilized as a therapeutic potential biomarker for disorders related to intronic expansion. Full article

The cellular prion protein (PrP^C) is studied in prion diseases, where its misfolded isoform (PrP^Sc) leads to neurodegeneration. PrP^C has also been implicated in several physiological functions. The protein is abundant in the nervous system, and it is critical for cell signaling in cellular communication, where it acts as a scaffold for various signaling molecules. The Reelin signaling pathway, implicated both in Alzheimer’s and prion diseases, engages Dab1, an adaptor protein influencing APP processing and amyloid beta deposition. Here, we show, using Prnp knockout models (Prnp^0/0), that PrP^C modulates Reelin signaling, affecting Dab1 activation and downstream phosphorylation in both neuronal cultures and mouse brains. Notably, Prnp^0/0 mice showed reduced responsiveness to Reelin, associated with altered Dab1 phosphorylation and Fyn kinase activity. Even though no direct interaction between PrP^C and Reelin/ApoER2 was found, Prnp^0/0 neurons showed lower NCAM levels, a well-established PrP^C interactor. Prion infection further disrupted the Reelin signaling pathway, thus downregulating Dab1 and Reelin receptors and altering Reelin processing, like Alzheimer’s disease pathology. These findings emphasize PrP^C indirect role in Dab1 signaling via the NCAM and Fyn pathways, which influence synaptic function and neurodegeneration in prion diseases. Full article

In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as “nutraceutical,” “mitochondrial dysfunction,” and “neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability. Full article

Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo’s concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) integrity and protection/maintenance/reestablishment in the stomach is translated to other organ therapy (cytoprotection → organoprotection) via the cytoprotection agent’s effect. Therefore, we defend stable gastric pentadecapeptide BPC 157 therapy’s efficacy and pleiotropic beneficial effects, along with its high safety (LD1 not achieved), against speculation of its negative impact, speculation of angiogenesis toward tumorigenesis, increased NO and eNOS, damaging free radical formation, and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease). Contrarily, in wound healing and general healing capabilities, as reviewed, as a cytoprotective agent and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system’s healing functions and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson’s disease and Alzheimer’s disease), and it presents prominent anti-tumor potential in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing “angiogenic privilege” (vs. angiogenesis/neovascularization/tumorigenesis), and it does not produce corneal neovascularization but rather opposes it. Per Folkman’s concept, it demonstrates an anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on the NO-level (increase vs. decrease), always combined with the counteraction of free radical formation, and, in mice and rats, BPC 157 therapy counteracts Parkinson’s disease-like and Alzheimer’s disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO’s cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions. Full article

Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that leads to disabilities such as difficulty moving and slowed cognitive processing. It is the leading non-traumatic cause of disability worldwide. MS also has a high potential to become a model for neurodegenerative diseases with a progression like Alzheimer’s or Parkinson’s. Cardiovascular diseases (CVDs) remain the leading cause of global deaths and have a considerable economic impact. The higher incidence of cardiovascular comorbidities in patients with MS compared to healthy individuals of the same age worsens the prognosis of neurological pathology, leading to a higher level of disability, poorer physical outcomes, higher depression scores, cognitive aging, and diminished quality of life. Classical observational studies often have questionable elements that can represent a source of error, making it difficult to establish a causal relationship between MS and CVD. Genetic studies, including genome-wide evaluation, may resolve this issue and may represent a topic for future research. We report the case of a 31-year-old male patient with a history of multiple sclerosis (MS) diagnosed seven years prior, who presented with acute chest pain upon returning from vacation. Despite the previous recommendation for disease-modifying therapy, the patient had discontinued treatment by personal choice. Electrocardiography (ECG) revealed ST-segment elevation in inferior leads, and emergent coronary angiography identified severe multi-vessel coronary artery disease (CAD), requiring immediate revascularization. This case highlights the potential cardiovascular risks in young patients with MS and the importance of continuous medical supervision. Full article