Molecular Neurobiology Research Papers - Academia.edu (original) (raw)

2025, Molecular and Cellular Biochemistry

In December 2019, the emergence and expansion of novel and infectious respiratory virus SARS-CoV-2 originated from Wuhan, China caused an unprecedented threat to the public health and became a global pandemic. SARS-CoV-2 is an enveloped, positive sense and single stranded RNA virus belonging to genera betacoronavirus, of Coronaviridae family. The viral genome sequencing studies revealed 75-80% similarity with SARS-CoV. SARS-CoV-2 mainly affects the lower respiratory system and may progress to pneumonia and Acute Respiratory Distress Syndrome (ARDS). Apart from lifethreatening situations and burden on the global healthcare system, the COVID-19 pandemic has imposed several challenges on the worldwide economics and livelihood. The novel pathogen is highly virulent, rapidly mutating and has a tendency to cross the species boundaries such as from bats to humans through the evolution and natural selection from intermediate host. In this review we tried to summarize the overall picture of SARS-CoV-2 including origin/ emergence, epidemiology, pathogenesis, genome organization, comparative analysis with other CoVs, infection and replication mechanism along with cellular tropism and immunopathogenesis which will provide a brief panoramic view about the virus and disease.

2025, Antioxidants & Redox Signaling

Significance: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. Recent Advances: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase f/d, casein kinase 2, phosphoinositide-3kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. Critical Issues: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. Future Directions: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. Antioxid. Redox Signal. 22,

2025

Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer's by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element ("CLEAR") in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.

2025, Alzheimer's & Dementia

2025, Molecular Neurobiology

Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in "TPP1, AGTPBP1, and PCDHGC4" genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological "neurodevelopmental disorders and neurodegenerative disorders" disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.

2025, Frontiers in Neurology

Background: Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms but there is a little evidence-based published material on the neurological manifestations of COVID-19. The purpose of this article is to review the spectrum of the various neurological manifestations and underlying associated pathophysiology in COVID-19 patients. Method: We conducted a review of the various case reports and retrospective clinical studies published on the neurological manifestations, associated literature, and related pathophysiology of COVID-19 using PUBMED and subsequent proceedings. A total of 118 articles were thoroughly reviewed in order to highlight the plausible spectrum of neurological manifestations of COVID 19. Every article was either based on descriptive analysis, clinical scenarios, correspondence, and editorials emphasizing the neurological manifestations either directly or indirectly. We then tried to highlight the significant plausible manifestations and complications that could be related to the pandemic. With little known about the dynamics and the presentation spectrum of the virus apart from the respiratory symptoms, this area needs further consideration. The neurological manifestations associated with COVID-19 such as Encephalitis, Meningitis, acute cerebrovascular disease, and Guillain Barré Syndrome (GBS) are of great concern. But in the presence of life-threatening abnormal vitals in severely ill COVID-19 patients, these are not usually underscored. There is a need to diagnose these manifestations at the earliest to limit long term sequelae. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from cerebrospinal fluid or brain tissues of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

2025, Frontiers in Psychiatry

Background: The coronavirus disease 2019 (COVID-19) pandemic represents a condition of increased vulnerability and frailty for elderly patients with Parkinson's disease (PD). Social isolation may worsen the burden of the disease and specifically exacerbate psychiatric symptoms, often comorbid with PD. This study aimed at identifying risk/protective factors associated with subjective worsening of psychiatric symptomatology during the COVID-19 outbreak in a sample of individuals with PD aged 65 years or older.Methods: Patients with PD routinely followed at the outpatient clinic of Gemelli University Hospital, Rome, were assessed for subjective worsening of psychiatric symptoms through a dedicated telephone survey, after Italy COVID-19 lockdown. Patients' medical records were reviewed to collect sociodemographic and clinical data, including lifetime psychiatric symptoms and pharmacological treatment.Results: Overall, 134 individuals were assessed and 101 (75.4%) reported lifeti...

2025, Complex Psychiatry

Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some SZ subjects. The pathophysiological role of mitochondrial dysfunction in SZ is based upon genomic analyses of both the mitochondrial genome and nuclear genes involved in mitochondrial function. Previous studies and preliminary data suggest SZ is associated with specific alleles and haplogroups of the mitochondrial genome, and also correlates with a reduction in mito...

2025, Molecular Neurobiology

Glucocorticoids affect learning and memory but the cellular mechanisms involved are poorly understood. The present studies tested if the stress-responsive glucocorticoid receptor (GR) is present and regulated within dendritic spines, and influences local signaling to the actin cytoskeleton. In hippocampal field CA1, 13% of synapses contained GR-immunoreactivity. Three-dimensional reconstructions of CA1 dendrites showed that GR aggregates are present in both spine heads and necks. Consonant with evidence that GRα mRNA associates with the translation regulator Fragile X Mental Retardation Protein (FMRP), spine GR levels were rapidly increased by group 1 mGluR activation and reduced in mice lacking FMRP. Treatment of cultured hippocampal slices with the GR agonist dexamethasone rapidly (15-30 min) increased total levels of phosphorylated (p) Cofilin and extracellular signal-regulated kinase (ERK) 1/2, proteins that regulate actin polymerization and stability. Dexamethasone treatment of adult hippocampal slices also increased numbers of PSD95+ spines containing pERK1/2, but reduced numbers of pCofilinimmunoreactive spines. Dexamethasone-induced increases in synaptic pERK1/2 were blocked by the GR antagonist RU-486. These results demonstrate that GRs are present in hippocampal spines where they mediate acute glucocorticoid effects on local spine signaling. Through effects on these actin regulatory pathways, GRs are positioned to exert acute effects on synaptic plasticity.

2025, Journal of Translational Medicine

Background: Recurrent pregnancy loss (RPL) occurs in 3-5% in about 30% of cases no cause can be found. Women with RPL show higher prevalence of undiagnosed gut disorders. Furthermore, in endometrial tissues of RPL women, higher expression of pro-inflammatory cytokines and Nalp-3 inflammasome has been observed. Aim of this study was to investigate whether an abnormal gut permeability might occur in RPL women and allow passage into systemic circulation of pro-inflammatory molecules able to induce endometrial inflammation. Methods: 70 women with idiopathic RPL and 30 healthy women were recruited at the Recurrent Pregnancy Loss Outpatient Unit of the Gemelli Hospital of Rome from March 2013 to February 2017. Enrolled women underwent 51 Cr-ethylene-diamine-tetraacetic acid absorption test to evaluate intestinal permeability. Sera obtained from enrolled women were analysed for lipopolysaccharide (LPS) by ELISA. Anxiety and depression state were evaluated by administering STAI-Y and Zung-SDS tests, respectively. Of all recruited individuals, 35 women with idiopathic RPL and 20 healthy controls accepted to undergo diagnostic hysteroscopy and endometrial biopsy. Endometrial lysates were investigated for inflammasome Nalp-3 by Western blot analysis, and caspase-1, IL-1β and IL-18 by ELISA, respectively. Results: Higher prevalence of abnormal intestinal permeability (P < 0.0001), increased circulating levels of LPS (P < 0.05), anxiety (P < 0.05) and depression (P < 0.05) were observed in RLP women compared to controls. Endometrial expression of Nalp-3, caspase-1 and IL-1β was significantly increased in RPL group (P < 0.0001; P < 0.05 and P < 0.001, respectively). IL-18 endometrial levels were not found to be higher in RPL cases. Statistically significant association between higher intestinal permeability and abnormally increased expression of endometrial Nalp-3, was observed in RPL (P < 0.01). Furthermore, higher LPS serum levels, a bacterial-derived activator of Nalp-3 complex, was shown to be statistically associated to abnormal endometrial expression of Nalp-3 inflammasome (P < 0.01) in RPL women. In women with RLP, leaky gut might occur and allow passage into circulation of immune triggers, potentially able to elicit endometrial innate immune response and, thus, to contribute to miscarriage pathogenesis. Diagnosis and treatment of intestinal disorders underlying leaky gut might improve endometrial environment and pregnancy outcome.

2025, Molecular Neurobiology

Development and normal physiology of the nervous system require proliferation and differentiation of stem and progenitor cells in a strictly controlled manner. The number of cells generated depends on the type of cell division, the cell cycle length, and the fraction of cells that exit the cell cycle to become quiescent or differentiate. The underlying processes are tightly controlled and modulated by cyclin-dependent kinases (Cdks) and their interactions with cyclins and Cdk inhibitors (CKIs). Studies performed in the nervous system with mouse models lacking individual Cdks, cyclins, and CKIs, or combinations thereof, have shown that many of these molecules control proliferation rates in a cell-type specific and time-dependent manner. In this review, we will provide an update on the in vivo studies on cyclins, Cdks, and CKIs in neuronal and glial tissue. The goal is to highlight their impact on proliferation processes during the development of the peripheral and central nervous system, including and comparing normal and pathological conditions in the adult.

2025, Molecular neurobiology

2025, Molecular Neurobiology

The mitochondrial theory of aging is characterized by mitochondrial electron transport chain dysfunction. As a hallmark of aging, an increasing number of investigations have attempted to improve mitochondrial function in both aging and age-related disease. Emerging from these attempts, methods involving mitochondrial isolation, transfusion, and transplantation have taken center stage. In particular, mitochondrial transfusion refers to the administration of mitochondria from healthy tissue into the bloodstream or into tissues affected by injury, disease, or aging. In this study, methods of mitochondrial isolation and transfusion were developed and utilized. First, we found a significant decrease (p < 0.05) in the expression of mitochondrial complex proteins (I-V) in aged (12 months old) mouse brain tissue (C57BL/6 mice) in comparison to healthy young brain tissue (1 month old). To investigate whether healthy young mitochondria taken from the liver could improve mitochondrial funct...

2025, Molecular Neurobiology

Mitochondrial dysfunction and oxidative stress are implicated in the neurodegenerative process in Parkinson's disease (PD). Moreover, c-Jun N-terminal kinase (JNK) plays an important role in dopaminergic neuronal death in substantia nigra pars compacta. Tauroursodeoxycholic acid (TUDCA) acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases. Here, we investigated the role of TUDCA in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in a mouse model of PD. We evaluated whether TUDCA modulates MPTPinduced degeneration of dopaminergic neurons in the nigrostriatal axis, and if that can be explained by regulation of JNK phosphorylation, reactive oxygen species (ROS) production, glutathione S-transferase (GST) catalytic activation, and Akt signaling, using C57BL/6 glutathione S-transferase pi (GSTP) null mice. TUDCA efficiently protected against MPTP-induced dopaminergic degeneration. We have previously demonstrated that exacerbated JNK activation in GSTP null mice resulted in increased susceptibility to MPTP neurotoxicity. Interestingly, pre-treatment with TUDCA prevented MPTP-induced JNK phosphorylation in mouse midbrain and striatum. Moreover, the antioxidative role of TUDCA was demonstrated in vivo by impairment of ROS production in the presence of MPTP. Finally, results herein suggest that the survival pathway activated by TUDCA involves Akt signaling, including downstream Bad phosphorylation and NF-κB activation. We conclude that TUDCA is neuroprotective in an in vivo model of PD, acting mainly by modulation of JNK activity M. Castro-Caldas and A. Neves Carvalho are joint first authors.

2025, Molecular neurobiology

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is acc...

2025, Molecular Neurobiology

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation BPrecision Behavioral Management^(PBM™) based on GARS test values and other prodopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

2025, Molecular Neurobiology

Although important information is available on the molecular mechanisms of long-term memory formation, little is known about the processes underlying memory persistence in the brain. Here, we report that persistent gene expression of CaMKIIδ isoform participates in object recognition long-lasting memory storage in mice hippocampus. We found that CaMKIIδ mRNA expression was sustained up to one week after training and paralleled memory retention. Antisense DNA infusion in the hippocampus during consolidation or even after consolidation impairs 7-day-but not 1-day-long memory, supporting a role of CaMKIIδ in memory persistence. CaMKIIδ gene expression was accompanied by long-lasting nucleosome occupancy changes at its promoter. This epigenetic mechanism is described for the first time in a memory process and offers a novel mechanism for persistent gene expression in neurons. CaMKIIδ protein is mainly present in nucleus and presynaptic terminals, suggesting a role in these subcellular compartments for memory persistence. All these results point to a key function of the sustained gene expression of this overlooked CaMKII isoform in long-lasting memories.

2025, Molecular neurobiology

A recent study from our lab has revealed a link between morphine-mediated autophagy and synaptic impairment. The current study was aimed at investigating whether morphine-mediated activation of astrocytes involved the ER stress/autophagy axis. Our in vitro findings demonstrated upregulation of GFAP indicating astrocyte activation with a concomitant increase in the production of proinflammatory cytokines in morphine-exposed human astrocytes. Using both pharmacological and gene-silencing approaches, it was demonstrated that morphine-mediated defective autophagy involved upstream activation of ER stress with subsequent downstream astrocyte activation via the μ-opioid receptor (MOR). In vivo validation demonstrated preferential activation of ER stress/autophagy axis in the areas of the brain not associated with pain such as the basal ganglia, frontal cortex, occipital cortex, and the cerebellum of morphine-dependent rhesus macaques, and this correlated with increased astrocyte activatio...

2025, Molecular neurobiology

Glutamate is the major excitatory transmitter of the vertebrate brain. It exerts its actions through the activation of specific plasma membrane receptors expressed both in neurons and in glial cells. Recent evidence has shown that glutamate uptake systems, particularly enriched in glia cells, trigger biochemical cascades in a similar fashion as receptors. A tight regulation of glutamate extracellular levels prevents neuronal overstimulation and cell death, and it is critically involved in glutamate turnover. Glial glutamate transporters are responsible of the majority of the brain glutamate uptake activity. Once internalized, this excitatory amino acid is rapidly metabolized to glutamine via the astrocyte-enriched enzyme glutamine synthetase. A coupling between glutamate uptake and glutamine synthesis and release has been commonly known as the glutamate/glutamine shuttle. Taking advantage of the established model of cultured Bergmann glia cells, in this contribution, we explored the...

2025, Arabian Journal of Chemistry

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline, with oxidative stress and neuroinflammation playing pivotal roles in its pathogenesis. Among potential candidates, vitamin B1 (Vit. B1) has gained attention for its neuroprotective potential due to antiinflammatory properties and antioxidant properties. This study investigates the therapeutic potential of Vit. B1 in an AD-like mouse model induced by scopolamine (SCOP). Administering Vit. B1 (300 µg/kg) with SCOP (1 mg/kg) is hypothesized to alleviate memory impairment and neuroinflammation. Behavioral tests, including Morris Water Maze (MWM) and Y-maze tests, revealing Vit. B1 ability to restore both long-term and short-term memory, especially in the prob test compared to SCOP-treated mice. Western blot analysis revealed Vit. B1′s role in reversing SCOP-induced changes by suppressing oxidative stress through NrF-2 and HO-1 proteins and inhibiting TLR4 receptor activation that upregulates TNF-α and NF-kβ, contributing to memory dysfunction. Molecular docking studies explored the binding affinity of TLR4 signalling pathway proteins. Results confirmed VitB1′s inhibitory effect on TLR4/md2 activation and its higher binding preference, underscored by experimental confirmation. Overall, these findings highlight Vit. B1′s neuroprotective potential as a therapeutic approach in AD and suggest a potential avenue for novel therapeutic strategies, warranting further preclinical and clinical research. Peer review under responsibility of King Saud University.

2025, Molecular Neurobiology

An imbalance of inflammatory/anti-inflammatory and oxidant/antioxidant molecules has been implicated in the demyelination and axonal damage in multiple sclerosis (MS). The current study aimed to evaluate the plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, sTNFR2, adiponectin, hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites, total plasma antioxidant capacity using the total radical-trapping antioxidant parameter (TRAP), sulfhydryl (SH) groups, as well as serum levels of zinc in 174 MS patients and 182 controls. The results show that MS is characterized by lowered levels of zinc, adiponectin, TRAP, and SH groups and increased levels of AOPP. MS was best predicted by a combination of lowered levels of zinc, adiponectin, TRAP, and SH groups yielding an area under the receiver operating characteristic (AUC/ROC) curve of 0.986 (±0.005). The combination of these four antioxidants with sTNFR2 showed an AUC/ ROC of 0.997 and TRAP, adiponectin, and zinc are the most important biomarkers for MS diagnosis followed at a distance by sTNFR2. Support vector machine with tenfold validation performed on the four antioxidants showed a training accuracy of 92.9% and a validation accuracy of 90.6%. The results indicate that lowered levels of those four antioxidants are associated with MS and that these antioxidants are more important biomarkers of MS than TNF-α signaling and nitro-oxidative biomarkers. Adiponectin, TRAP, SH groups, zinc, and sTNFR2 play a role in the pathophysiology of MS, and a combination of these biomarkers is useful for predicting MS with high sensitivity, specificity, and accuracy. Drugs that increase the antioxidant capacity may offer novel therapeutic opportunities for MS.

2025, Molecular neurobiology

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patien...

2025, Molecular Neurobiology

A milestone in Huntington's disease (HD) research is represented by the identification of the causative gene. With the genetics at hand, a series of transgenic cellular and animal models has been developed, which has greatly contributed to understanding of HD. All these models are described in this review, and are compared to each other, along with the information they have generated. Although the mechanism by which progressive loss of striatal neurons occurs in HD remains uncertain, hypotheses on mutant huntingtin toxicity involve impaired vescicular trafficking, transcriptional dysregulation, and/or activation of apoptotic pathways. The development of inducible HD mice has shown that neurodegeneration in HD may be at least partially blocked. Although traditionally considered a "gain-of-function" disease, the recent finding that normal huntingtin has an important role in neuronal survival suggests that loss of function of the normal protein might contribute to HD as well, also discloseing new perspectives on the therapeutical approach to the pathology.

2025, Molecular Neurobiology

2025, PubMed

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.

2025, Molecular Neurobiology

Previous studies have revealed that the infectious scrapie isoform of prion protein (PrPSc) harbored in the skin tissue of patients or animals with prion diseases can be amplified and detected through the serial protein misfolding cyclic amplification (sPMCA) or real-time quaking-induced conversion (RT-QuIC) assays. These findings suggest that skin PrPSc-seeding activity may serve as a biomarker for the diagnosis of prion diseases; however, its utility as a biomarker for prion therapeutics remains largely unknown. Cellulose ethers (CEs, such as TC-5RW), widely used as food and pharmaceutical additives, have recently been shown to prolong the lifespan of prion-infected mice and hamsters. Here we report that in transgenic (Tg) mice expressing hamster cellular prion protein (PrPC) infected with the 263K prion, the prion-seeding activity becomes undetectable in the skin tissues of TC-5RW-treated Tg mice by both sPMCA and RT-QuIC assays, whereas such prion-seeding activity is readily det...

2025

To address the issue of feeding outdoor cats, this study designed an intelligent cat recognition and feeding system. In terms of hardware, it integrates a Raspberry Pi 4B with OpenCV to combine ultrasonic sensor cameras, servos, and pressure sensors, forming a dynamic monitoring, characteristic identification, and precise feeding operation process. In software, OpenCV is used for cat face recognition, and Python scripts are employed to coordinate the work of sensors and actuators. The response time of the system can be controlled to be below 4 seconds. In the accurate recognition and feeding management of stray cats, the effect is quite significant. The adoption of low-cost hardware and lightweight control strategies has endowed an operational approach that is both engineering innovative and socially meaningful, enhancing the efficiency of outdoor stray cat management and facilitating the search for lost pets.

2025, Molecular Neurobiology

Food composition influences stroke risk, but its effects on ischemic injury and neurological deficits are poorly examined. While severe reduction of protein content was found to aggravate neurological impairment and brain injury as a consequence of combined energy-protein malnutrition, moderate protein restriction not resulting in energy deprivation was recently suggested to protect against perinatal hypoxia-ischemia. Male C57BL6/j mice were exposed to moderate protein restriction by providing a normocaloric diet containing 8% protein (control: 20% protein) for 7, 14, or 30 days. Intraluminal middle cerebral artery occlusion was then induced. Mice were sacrificed 24 h later. Irrespective of the duration of food modification (that is, 7-30 days), protein restriction reduced neurological impairment of ischemic mice revealed by a global and focal deficit score. Prolonged protein restriction over 30 days also reduced infarct volume, brain edema, and blood-brain barrier permeability and increased the survival of NeuN+ neurons in the core of the stroke (i.e., striatum). Neuroprotection by prolonged protein restriction went along with reduced brain infiltration of CD45+ leukocytes and reduced expression of inducible NO synthase and interleukin-1β. As potential mechanisms, increased levels of the NAD-dependent deacetylase sirtuin-1 and anti-oxidant glutathione peroxidase-3 were noted in ischemic brain tissue. Irrespective of the protein restriction duration, a shift from pro-oxidant oxidative stress markers (NADPH oxidase-4) to anti-oxidant markers (superoxide dismutase-1/2, glutathione peroxidase-3 and catalase) was found in the liver. Moderate protein restriction protects against ischemia in the adult brain. Accordingly, dietary modifications may be efficacious strategies promoting stroke outcome.

2025, Molecular Neurobiology

Axotomy-induced synaptic stripping modulates survival and axon regeneration of injured motoneurons. Celsr2 is supposed to mediate homophilic interactions of neighboring cells during development, and its role in synaptic stripping remains unknow. In a model of brachial plexus avulsion, Celsr2 knockout improved functional recovery, motoneuron survival, and axon regeneration. Celsr2 was indicated to express in spinal motoneurons, excitatory and inhibitory interneurons, astrocytes, and a subset of oligodendrocytes using Celsr2 LacZ mice. Double immunostaining showed that the coverage of inhibitory and excitatory vesicles on injured motoneurons were remarkably reduced after injury, whereas more inhibitory vesicles were maintained in Celsr2 -/-mutants than control mice. In the ultrastructure, the density of inhibitory F-boutons on injured motoneurons was higher in Celsr2 -/-mutants than controls. Conditional knockout of Celsr2 in astrocytes or oligodendrocytes showed the similar axotomy-induced synaptic withdrawal to the control. RNAseq of injured spinal samples identified 12 MHC I molecules with significant changes between Celsr2 -/-and control mice. After injury, expression of MHC I surrounding injured motoneurons was increased, particularly high in Celsr2 -/- mutants. In conclusion, Celsr2 knockout enhances MHC I signaling, alleviates inhibitory synaptic stripping cell-autonomously, and contributes to motoneuron survival and regeneration, and Celsr2 is a potential target for neural repair.

2025, Molecular Neurobiology

Inactivation of Celsr3 in the forebrain results in defects of longitudinal axonal tracts such as the corticospinal tract. In this study, we inactivated Celsr3 in the brainstem using En1-Cre mice (Celsr3 cKO) and analyzed axonal and behavioral phenotypes. Celsr3 cKO animals showed an 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons in spinal segments, associated with increased branching of dopaminergic fibers in the ventral horn. Decreases of spinal motoneurons, neuromuscular junctions, and electromyographic signal amplitude of the biceps were also found in mutant animals. Mutant mice had impaired motor coordination and defective response to heavy mechanical stimulation, but no disability in walking and food pellet handling. Transsynaptic tracing demonstrated that rubrospinal axons synapse on spinal neurons in the deep layer of the dorsal horn, and mechanical stimulation of hindpaws induced strong calcium signal of red nuclei in control mice, which was less prominent in mutant mice. In conclusion, Celsr3 regulates development of spinal descending axons and the motor network in cell and non-cell autonomous manners, and the maturation of the rubrospinal system is required for motor coordination and response to mechanical stimulation.

2025

Dysregulated A to I RNA editing and non-coding RNAs in

2025, Molecular Neurobiology

The β-amyloid peptide (Aβ) is found as amyloid fibrils in senile plaques, a typical hallmark of Alzheimer’s disease (AD). However, intermediate soluble oligomers of Aβ are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant Aβ have shown that hexameric Aβ in particular acts as a critical nucleus for Aβ self-assembly. We recently isolated hexameric Aβ assemblies from a cellular model, and demonstrated their ability to enhance Aβ aggregation in vitro. Here, we report the presence of similar hexameric-like Aβ assemblies across several cellular models, including neuronal-like cell lines. In order to better understand how they are produced in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in their formation. PS1 and PS2 are the catalytic subunits of the γ-secretase complex that generates Aβ. Using CRISPR-Cas9 to knockdown each of the two presenilins in neuronal-like cell lines, we observed a direct lin...

2025, Molecular Neurobiology

Anabolic-androgenic steroids (AAS) abuse is often associated with a wide spectrum of adverse effects. These drugs are frequently abused by adolescents and athletes for esthetic purposes, as well as for improvement of their endurance and performances. In this literature review, we evaluated the correlation between AAS and anxiety or aggression. Two pathways are thought to be involved in AAS-induced behavioral disorders. Direct pathway via the amygdalo-fugal pathway, which connects the central nucleus of the amygdala to the brainstem, is involved in cognitive-emotive and homeostatic processes. The latter is modified by chronic AAS use, which subsequently leads to increased anxiety. Indirect pathways via the serotonergic, dopaminergic, and glutamatergic signals which are modified by AAS abuse in latero-anterior hypothalamus and can mediate the aggressive behavior. In conclusion, the molecular mechanisms underlying the behavioral alterations following AAS abuse is unclear and remains ambiguous as additional long-term studies aimed to understand the precise mechanisms are required.

2025, Molecular Neurobiology

The current pharmacological treatment for Parkinson's disease (PD) is focused on symptom alleviation rather than disease prevention. In this study, we look at a new strategy to neuroprotection that focuses on nutrition, by a supplementation with Açai berry in an experimental models of PD. Daily orally supplementation with Açai berry dissolved in saline at the dose of 500 mg/kg considerably reduced motor and non-motor symptom and neuronal cell death of the dopaminergic tract induced by 4 injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, Açai berry administration reduced α-synuclein aggregation in neurons, enhanced tyrosine hydroxylase and dopamine transporter activities, and avoided dopamine depletion. Moreover, Açai berry administration was able to reduce astrogliosis and microgliosis as well as neuronal death. Its beneficial effects could be due to its bioactive phytochemical components that are able to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) by counteracting the oxidative stress and neuroinflammation that are the basis of this neurodegenerative disease.

2025, Molecular Neurobiology

Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration of dopaminergic neurons. Aging is a major risk factor for idiopathic PD. Several prior studies examined the neuroprotective effects of palmitoylethanolamide (PEA), alone or combined with antioxidants, in a model of PD induced by the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here, we analyzed the pretreatment effect of micronized PEA (PEAm) on neuroinflammation and neuronal cell death in the MPTP model. Male CD mice (21 months of age) were pre-treated for 60 days with PEAm. After this time, they received four intraperitoneal injections of MPTP over a 24-h period and were killed 7 days later. On the 8th day, brains were processed. Pretreatment with PEAm ameliorated behavioral deficits and the reductions in expression of tyrosine hydroxylase and dopamine transporter, while blunting the upregulation of α-synuclein and β3-tubulin in the substantia nigra after MPTP induction. Moreover, PEAm reduced proinflammatory cytokine expression and showed a pro-neurogenic effect in hippocampus. These findings propose this strategy as a valid approach to prevent neurodegenerative diseases associated with old age.

2025, Molecular Neurobiology

Parkinson's disease (PD) is a multi-layered progressive neurodegenerative disease. Signature motor system impairments are accompanied by a variety of other symptoms such as mood, sleep, metabolic, and cognitive disorders. Interestingly, social cognition impairments can be observed from the earliest stages of the disease, prior to the onset of the motor symptoms. In this study, we investigated age-related reductions in sociability and social memory in the A53T mouse model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we examined astrogliosis and inflammation markers and parvalbumin expression in medial pre-frontal cortex (mPFC), part of the brain responsible for social cognition regulation. Finally, we used DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) for the stimulation and inhibition of orexin neuronal activity to modulate sociability and social memory in A53T mice. We observed that social cognition impairment in A53T mice is accompanied by an increase in astrogliosis and inflammation markers, in addition to loss of parvalbumin neurons and inhibitory pre-synaptic terminals in the mPFC. Moreover, DREADD-induced activation of orexin neurons restores social cognition in the A53T mouse model of PD. Social cognition is severely affected in the early stages of Parkinson's disease. In this study, we identified the A53T mouse as a model of social cognitive impairment in PD. Observed alterations in sociability and social memory are accompanied by loss of parvalbumin positive neurons and loss of inhibitory input to mPFC. Stimulating orexin neurons using a chemogenetic approach (DREADDs) ameliorated social cognitive impairment. This study identifies a role for orexin neurons in social cognition in PD and suggests potential therapeutic targets for PD-related social cognition impairments.

2025, Molecular Neurobiology

Phosphorylation of α-synuclein (aSyn) on serine 129 is one of the major post-translation modifications found in Lewy bodies, the typical pathological hallmark of Parkinson's disease. Here, we found that both PLK2 and PLK3 phosphorylate aSyn on serine 129 in yeast. However, only PLK2 increased aSyn cytotoxicity and the percentage of cells presenting cytoplasmic foci. Consistently, in mammalian cells, PLK2 induced aSyn phosphorylation on serine 129 and induced an increase in the size of the inclusions. Our study supports a role for PLK2 in the generation of aSyn inclusions by a mechanism that does not depend directly on serine 129 phosphorylation.

2025, Molecular Neurobiology

is implicated in Parkinson's disease and several other neurodegenerative disorders. To date, the function and intracellular dynamics of aSyn are still unclear. Here, we tracked the dynamics of aSyn using photoactivatable green fluorescent protein as a reporter. We found that the availability of the aSyn N terminus modulates its shuttling into the nucleus. Interestingly, familial aSyn mutations altered the dynamics at which the protein distributes throughout the cell. Both the A30P and A53T aSyn mutations increase the speed at which the protein moves between the nucleus and cytoplasm, respectively. We also found that specific kinases potentiate the shuttling of aSyn between nucleus and cytoplasm. A mutant aSyn form that blocks S129 phosphorylation, S129A, results in the formation of cytoplasmic inclusions, suggesting phosphorylation modulates aggregation in addition to modulating aSyn intracellular dynamics. Finally, we found that the molecular chaperone HSP70 accelerates the entry of aSyn into the nuclear compartment.

2025, Molecular Neurobiology

Three early signals of asymmetry have been described to occur in a single neurite of neurons at stage 2 of differentiation (before polarization) and shown to be essential for neuronal polarization: (i) accumulation of stable microtubules, (ii) enrichment of the plasma membrane with activatable IGF-1r, and (iii) polarized transport of the microtubular motor KIF5C. Here, we studied the possible relationship between these three phenomena. Our results show that the activatable (membrane-inserted) IGF-1r and stable microtubules accumulate in the same neurite of cells at stage 2. The polarized insertion of IGF-1r depends on microtubule dynamics as shown using drugs which modify microtubule stability. Silencing of KIF5C expression prevents the polarized insertion of IGF-1r into the neuronal plasmalemma and neuronal polarization. Syntaxin 6 and VAMP4, necessary for the polarized insertion of the IGF-1r, are associated to vesicles carried by the microtubular motor KIF5C and is transported preferentially to the neurite where KIF5C accumulates. We conclude that the enrichment of stable microtubules in the future axon enhances KIF5C-mediated vesicular transport of syntaxin 6 and VAMP4, which in turn mediates the polarized insertion of IGF-1r in the plasmalemma, a key step for neuronal polarization. We herewith establish a mechanistic link between three early polarity events necessary for the establishment of neuronal polarity.

2025, Molecular Neurobiology

Traumatic brain injury (TBI) is a major public health concern in the USA. There are approximately 2.5 million brain injuries annually, 90% of which may be classified as mild since these individuals do not display clear morphological abnormalities following injury on imaging. The majority of individuals develop neurocognitive deficits such as learning and memory impairment and recovery occurs over 3 to 6 months after mild TBI (mTBI). The hippocampus is highly susceptible to injury from mTBI due to the anatomic localization and has been implicated in the neurocognitive impairments after mTBI. Here, we investigated whether the mTBI-induced morphological and pathophysiological alterations of GABAergic interneurons in the CA1 subfield of the hippocampus recovers after 30 days in the controlled cortical impact (CCI) model of TBI. Design-based stereology shows a significant reduction in the number of GABAergic interneurons 7 days after CCI. However, the number of GABAergic interneurons is not significantly reduced at 30 days after CCI. The total number of neurons is not altered over the course of 30 days. GABAergic inhibitory currents in the CA1 subfield also show that, although there is a significant reduction in the CCI group at 7 days, the currents are not significantly different from sham controls at 30 days. We suggest that the recovery of GABAergic function in the CA1 subfield of the hippocampus observed 30 days after CCI is one of the mechanisms associated with the recovery of memory after mTBI.

2025, Molecular Neurobiology

Our previous reports indicate that the electron transfer chain and F o F 1 -ATP synthase are functionally expressed in myelin sheath, performing an extramitochondrial oxidative phosphorylation (OXPHOS), which would provide energy to the nerve axon. This supports the idea that myelin plays a trophic role for the axon. Although the four ETC complexes and ATP synthase are considered exquisite mitochondrial proteins, they are found ectopically expressed in several membranous structures. This study was designed to understand when and how the mitochondrial OXPHOS machinery is embedded in myelin, following myelinogenesis in the rat, which starts at birth and continues until the first month of age. Rats were sacrificed at different time points (from day 5 to 90 post birth). Western blot, immunofluorescence microscopy, luminometric, and oximetric analyses show that the isolated myelin starts to show OXPHOS components around the 11th day after birth and increases proportionally to the rat age, becoming similar to those of adult rat around the 30-third day. Interestingly, WB data show the same temporal relationship between myelinogenesis and appearance of proteins involved in mitochondrial fusion and cellular trafficking. It may be speculated that the OXPHOS complexes may be transferred to the endoplasmic reticulum membrane (known to interact with mitochondria) and from there through the Golgi apparatus to the forming myelin membrane.

2025, Molecular Neurobiology

Recent advances in life sciences suggest that human and rodent cell responses to stimuli might differ significantly. In this context, the results achieved in neurotoxicology and biomedical research practices using neural networks obtained from mouse or rat primary culture of neurons would benefit of the parallel evaluation of the same parameters using fully differentiated neurons with a human genetic background, thus emphasizing the current need of neuronal cells with human origin. In this work, we developed a human functionally active neural network derived by human neuroblastoma cancer cells genetically engineered to overexpress NDM29, a non-coding RNA whose increased synthesis causes the differentiation toward a neuronal phenotype. These cells are here analyzed accurately showing functional and morphological traits of neurons such as the expression of neuron-specific proteins and the possibility to generate the expected neuronal current traces and action potentials. Their morphometrical analysis is carried out by quantitative phase microscopy showing soma and axon sizes compatible with those of functional neurons. The ability of these cells to connect autonomously forming physical junctions recapitulates that of hippocampal neurons, as resulting by connect-ability test. Lastly, these cells self-organize in neural networks able to produce spontaneous firing, in which spikes can be clustered in bursts. Altogether, these results show that the neural network obtained by NDM29-dependent differentiation of neuroblastoma cells is a suitable tool for biomedical research practices.

2025, Molecular Neurobiology

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.

2025, Molecular Neurobiology

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

2025, Molecular Neurobiology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and grim prognosis. Over the last decade, studies on neurodegenerative diseases pointed on the role of glia in supporting the proper function of neurons. Particularly, oligodendrocytes were shown to be essential through myelin production and supplying axons with energy metabolites via monocarboxylate transporters (MCT). We have used dogs with naturally occurring degenerative myelopathy (DM) which closely resembles features observed in human ALS. We have performed two types of analysis of spinal cord tissue samples: histology and molecular analysis. Histology included samples collected from dogs that succumbed to the DM at different disease stages, which were compared to age-matched controls as well as put in the context of young spinal cords. Molecular analysis was performed on spinal cords with advanced DM and age-matched samples and included real-time PCR analysis of selected gene products related to the function of neurons, oligodendrocytes, myelin, and MCT. Demyelination has been detected in dogs with DM through loss of eriochrome staining and decreased expression of genes related to myelin including MBP, Olig1, and Olig2. The prominent reduction of MCT1 and MCT2 and increased MCT4 expression is indicative of disturbed energy supply to neurons. While Rbfox3 expression was not altered, the ChAT production was negatively affected. DM in dogs reproduces main features of human ALS including loss of motor neurons, dysregulation of energy supply to neurons, and loss of myelin, and as such is an ideal model system for highly translational studies on therapeutic approaches for ALS.

2025, Molecular Neurobiology

The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB 1 type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB 2 cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer's disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.

2025, International Journal of Applied Pharmaceutics

Parkinson's Disease (PD), a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, is closely associated with neuroinflammation mediated by exosomes. This review discusses the role of exosomes in the modulation of neuroinflammatory processes in PD. Small Extracellular Vesicles (EVs) are exosomes that communicate between cells by transporting proteins, lipids, and RNAs that affect neuronal health. We investigated how exosomes propagate misfolded α-synuclein and proinflammatory mediators, leading to microglial activation and neurodegeneration. The key questions addressed include the following: (1) How do exosomes promote the spread of α-synuclein pathology? (2) What molecular pathways drive exosome-mediated neuroinflammation in PD? (3) Can exosomes serve as diagnostic biomarkers or therapeutic vehicles? By analyzing these mechanisms, this review underscores the dual role of exosomes in exacerbating disease progression and their potential for innovative treatments. This finding highlights the challenges in current methodologies and future prospects of exosome-targeted therapy in PD.

2025, Molecular Neurobiology

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

2025, Thai J Vet Med

Tumors in oral cavity either benign or malignant are often found in dogs. Despite the increasing number of studies of gene expression associated with canine oral cavity diseases, reference gene selection for normalizing target genes has not been performed. The objective of the present study was to identify potential reference genes in canine oral tumors, including epulis, ameloblastoma, oral melanoma, oral squamous cell carcinoma, etc. Suitability of 6 candidate reference genes, beta-actin (ACTB), beta-2-microglobulin (B2M), glyceraldehydes-3-phosphate dehydrogenase (GAPDH), ribosomal subunit L13a (RPL13a), ribosomal protein S5 (RPS5) and ribosomal protein S19 (RPS19), was evaluated with 5 algorithms, geNorm, Normfinder, BestKeeper, the comparative ΔCt method and RefFinder. Except Bestkeeper, most algorithms showed that a cohort of RPS5, RPS19 and ACTB was most suitable to normalize target genes. Since some algorithms did not show the same ranks of reference genes, it is necessary to normalize target genes against more than 1 reference gene with more than 1 algorithm. In conclusion, this work suggests that ACTB in combination with RPS19 and RPS5 are validated to be used as reference genes for expression study in canine oral tumors. These reference genes will increase the reliability of any qRT-PCR gene expression analysis of canine oral tumor and cancer in several aspects such as clinical diagnosis, prognosis and drug testing.