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Scientific Reports Jun 2024We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets...
We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early Tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower p(181)Tau and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.
Topics: Alzheimer Disease; Humans; Male; Female; tau Proteins; Biomarkers; Polymorphism, Single Nucleotide; Aged; Synapses; Synaptosomal-Associated Protein 25; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Aged, 80 and over; Synaptotagmin I; Brain; Middle Aged
PubMed: 38926456
DOI: 10.1038/s41598-024-65104-2 -
Cellular Signalling Jun 2024Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia...
Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) tauopathies. We have previously reported that two tau transgenic mouse models, L1 and L66, produce different phenotypes resembling AD and FTD, respectively. The AD-like L1 model expresses the truncated core aggregation domain of the AD paired helical filament (PHF) form of tau (tau296-390) whereas the FTD-like L66 model expresses full-length tau carrying two mutations at P301S/G335D. We have used synaptosomes isolated from these mice to investigate K-evoked glutamate release and, if abnormal, to determine responsiveness to hydromethylthionine, a tau aggregation inhibitor previously shown to reduce tau pathology in these models. We report that the transgenes in these two mouse lines cause opposite abnormalities in glutamate release. Over-expression of the core tau unit in L1 produces a significant reduction in glutamate release and a loss of Ca-dependency compared with wild-type control mice. Full-length mutant tau produces an increase in glutamate release that retains normal Ca-dependency. Chronic pre-treatment with hydromethylthionine normalises both reduced (L1) and excessive glutamate (L66) and restores normal Ca-dependency in L1 mice. This implies that both patterns of impairment are the result of tau aggregation, but that the direction and Ca-dependency of the abnormality is determined by expression of the disease-specific transgene. Our results lead to the conclusion that the tauopathies need not be considered a single entity in terms of the downstream effects of pathological aggregation of tau protein. In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD.
PubMed: 38909930
DOI: 10.1016/j.cellsig.2024.111269 -
Journal of Oral Biosciences Jun 2024Botulinum toxin type A (BTX-A), produced by the gram-positive anaerobic bacterium Clostridium botulinum, acts by cleaving synaptosome-associated protein-25 (SNAP-25), an... (Review)
Review
BACKGROUND
Botulinum toxin type A (BTX-A), produced by the gram-positive anaerobic bacterium Clostridium botulinum, acts by cleaving synaptosome-associated protein-25 (SNAP-25), an essential component of the presynaptic neuronal membrane that is necessary for fusion with the membrane proteins of neurotransmitter-containing vesicles. Recent studies have highlighted the efficacy of BTX-A in treating chronic pain conditions, including lower back pain, chronic neck pain, neuropathic pain, and trigeminal neuralgia, particularly when patients are unresponsive to traditional painkillers. This review focuses on the analgesic effects of BTX-A in various chronic pain conditions, with a particular emphasis on the orofacial region.
HIGHLIGHT
This review focuses on the mechanisms by which BTX-A induces analgesia in patients with inflammatory and temporomandibular joint pain. This review also highlights the fact that BTX-A can effectively manage neuropathic pain and trigeminal neuralgia, which are difficult-to-treat chronic pain conditions. Herein, we present a comprehensive assessment of the central analgesic effects of BTX-A and a discussion of its various applications in clinical dental practice.
CONCLUSION
BTX-A is an approved treatment option for various chronic pain conditions. Although there is evidence of axonal transport of BTX-A from peripheral to central endings in motor neurons, the precise mechanism underlying its pain-modulating effects remains unclear. This review discusses the evidence supporting the effectiveness of BTX-A in controlling chronic pain conditions in the orofacial region. BTX-A is a promising therapeutic agent for treating pain conditions that do not respond to conventional analgesics.
PubMed: 38908515
DOI: 10.1016/j.job.2024.06.004 -
Neurobiology of Aging Jun 2024Traumatic brain injury (TBI) and Alzheimer's disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive...
Traumatic brain injury (TBI) and Alzheimer's disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (AD n=110), or without (AD, n=110) and compared baseline CSF concentrations of amyloid beta 1-42 (Aβ42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between AD and AD patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.
PubMed: 38908030
DOI: 10.1016/j.neurobiolaging.2024.06.001 -
Cancer Science Jun 2024Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality...
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
PubMed: 38889208
DOI: 10.1111/cas.16239 -
JCI Insight Jun 2024Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and...
Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice have been shown to appear overweight shortly after weaning. Here, we analyzed serum biochemistry and histology of adipose and liver tissues to determine the incidence of obesity and NAFLD in trappc9-deficient mice and combined transcriptomic and proteomic analyses, pharmacological studies, and biochemical and histological examinations of postmortem mouse brains to unveil mechanisms involved. We found that trappc9-deficient mice presented with systemic glucose homeostatic disturbance, obesity and NAFLD, which were relieved upon chronic treatment combining dopamine receptor D2 (DRD2) agonist quinpirole and DRD1 antagonist SCH23390. Blood glucose homeostasis in trappc9-deficient mice was restored upon administrating quinpirole alone. RNA-sequencing analysis of DRD2-containing neurons and proteomic study of brain synaptosomes revealed signs of impaired neurotransmitter secretion in trappc9-deficient mice. Biochemical and histological studies of mouse brains showed that trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine synapse formation.
PubMed: 38889014
DOI: 10.1172/jci.insight.181339 -
Journal of Visualized Experiments : JoVE May 2024Microglia play a pivotal role in synaptic refinement in the brain. Analysis of microglial engulfment of synapses is essential for comprehending this process; however,...
Microglia play a pivotal role in synaptic refinement in the brain. Analysis of microglial engulfment of synapses is essential for comprehending this process; however, currently available methods for identifying microglial engulfment of synapses, such as immunohistochemistry (IHC) and imaging, are laborious and time-intensive. To address this challenge, herein we present in vitro and in vivo* assays that allow fast and high-throughput quantification of microglial engulfment of synapses using flow cytometry. In the in vivo* approach, we performed intracellular vGLUT1 staining following fresh cell isolation from adult mouse brains to quantify engulfment of vGLUT1 synapses by microglia. In the in vitro synaptosome engulfment assay, we used freshly isolated cells from the adult mouse brain to quantify the engulfment of pHrodo Red-labeled synaptosomes by microglia. These protocols together provide a time-efficient approach to quantifying microglial engulfment of synapses and represent promising alternatives to labor-intensive image analysis-based methods. By streamlining the analysis, these assays can contribute to a better understanding of the role of microglia in synaptic refinement in different disease models.
Topics: Animals; Microglia; Mice; Synapses; Flow Cytometry; Vesicular Glutamate Transport Protein 1; Synaptosomes; Brain
PubMed: 38884489
DOI: 10.3791/66639 -
Frontiers in Immunology 2024Significant neurologic morbidity is caused by pediatric cerebrospinal fluid (CSF) shunt infections. The underlying mechanisms leading to impaired school performance and...
INTRODUCTION
Significant neurologic morbidity is caused by pediatric cerebrospinal fluid (CSF) shunt infections. The underlying mechanisms leading to impaired school performance and increased risk of seizures are unknown, however, a better understanding of these mechanisms may allow us to temper their consequences. Recent evidence has demonstrated important roles for complement proteins in neurodevelopment and neuroinflammation.
METHODS
We examined complement activation throughout () central nervous system (CNS) catheter infection. In addition, based on accumulating evidence that C3 plays a role in synaptic pruning in other neuroinflammatory states we determined if C3 and downstream C5 led to alterations in synaptic protein levels. Using our murine model of catheter infection we quantified levels of the complement components C1q, Factor B, MASP2, C3, and C5 over the course of infection along with bacterial burdens.
RESULTS
We found that MASP2 predominated early in catheter infection, but that Factor B was elevated at intermediate time points. Unexpectedly C1q was elevated at late timepoints when bacterial burdens were low or undetectable. Based on these findings and the wealth of information regarding the emerging roles of C1q in the CNS, this suggests functions beyond pathogen elimination during CNS catheter infection. To identify if C3 impacted synaptic protein levels we performed synaptosome isolation and quantified levels of VGLUT1 and PSD95 as well as pre-, post- and total synaptic puncta in cortical layer V of C3 knockout (KO) and wild type mice. We also used C5 KO and wild type mice to determine if there was any difference in pre-, post- and total synaptic puncta.
DISCUSSION
Neither C3 nor C5 impacted synaptic protein abundance. These findings suggest that chronic elevations in C1q in the brain that persist once CNS catheter infection has resolved may be modulating disease sequalae.
Topics: Animals; Staphylococcus epidermidis; Mice; Complement C1q; Staphylococcal Infections; Catheter-Related Infections; Disease Models, Animal; Mice, Inbred C57BL; Male; Complement Activation; Female; Chronic Disease; Mice, Knockout
PubMed: 38881889
DOI: 10.3389/fimmu.2024.1342467 -
Neurochemistry International Jun 2024Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B (thiamine) deficiency. However, the...
Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2-C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogs of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.
PubMed: 38880231
DOI: 10.1016/j.neuint.2024.105791 -
Journal of Neuroimmune Pharmacology :... Jun 2024The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the...
The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the emerging public health challenge of understanding and treating POE children. We examined two scenarios using preclinical models: offspring exposed to oxycodone (OXY) in utero (IUO) and acute postnatal OXY (PNO). We hypothesized exposure to OXY during pregnancy primes offspring for neurodevelopmental deficits and severity of deficits is dependent on timing of exposure. Notable findings include reduced head size and brain weight in offspring. Molecular analyses revealed significantly lower levels of inflammasome-specific genes in the prefrontal cortex (PFC). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) highlighted the enrichment of genes associated with mitochondrial and synapse dysfunction in POE offspring. Western blot analysis validated IPA predictions of mitochondrial dysfunction in PFC-derived synaptosomes. Behavioral studies identified significant social deficits in POE offspring. This study presents the first comparative analysis of acute PNO- and IUO-offspring during early adolescence finding acute PNO-offspring have considerably greater deficits. The striking difference in deficit severity in acute PNO-offspring suggests that exposure to opioids in late pregnancy pose the greatest risk for offspring well-being.
Topics: Animals; Oxycodone; Pregnancy; Female; Prenatal Exposure Delayed Effects; Male; Analgesics, Opioid; Behavior, Animal; Rats; Rats, Sprague-Dawley; Neurodevelopmental Disorders; Prefrontal Cortex
PubMed: 38874861
DOI: 10.1007/s11481-024-10129-7