Assessment of meso- and microplastics distribution in coastal sediments and waters at the middle estuary of the Rio De La Plata, Argentina (SW Atlantic Ocean).

Estuarine coastal water and sediments collected from multiple locations within the middle Río de la Plata (RDLP) estuary were analyzed in order to identify the presence of microplastics (MPs, <5 mm) and mesoplastics (MePs, 5-25 mm) in one of the most significant estuaries in the Southwestern Atlantic. The present study represents one of the first researches to survey MPs and MePs contamination in key stations at RDLP estuary. Average concentrations of 14.17 ± 5.50 MPs/L and 10.00 MePs/L were detected in water samples, while 547.83 ± 620.06 MPs/kg (dry weight) and 74.23 ± 47.29 MePs/kg d.w. were recorded in sediments. The greatest abundances were observed in the more anthropized areas, near urban settlements. Fibers were the most conspicuous plastic items in water and sediments, followed by fragments. On the other hand, surface sediments, and 50 cm and 100 cm-depth sediments also presented MPs and MePs indicating they could serve as a stratigraphic indicator for recently formed sediments. The main polymer type identified were acrylic fibers, followed by polypropylene (PP) and polyethylene terephthalate (PET). Besides, SEM-EDX detected the presence of Si, Fe, Ti, Al and Cl onto the plastics' surface. These elements may serve as additives to enhance the plastics' properties, such as in the case of Ti, or they could originate from the environment, like biogenic Si or Fe, and Al possibly as a component of the suspended particles or sediments adhered to the micro or meso plastics. Finally, the results of the present study showed that MPs and MePs are commonly found in waters and also tend to be trapped in sediments of the RDLP estuary supporting the assertion that these areas play a substantial role in influencing the transport, dispersion, and buildup of MPs in estuarine regions.

Hippocampal synaptic failure is an early event in experimental parkinsonism with subtle cognitive deficit.

Learning and memory mainly rely on correct synaptic function in the hippocampus and other brain regions. In Parkinson's disease, subtle cognitive deficits may even precede motor signs early in the disease. Hence, we set out to unravel the earliest hippocampal synaptic alterations associated with human α-synuclein overexpression prior to and soon after the appearance of cognitive deficits in a parkinsonism model. We bilaterally injected adeno-associated viral vectors encoding A53T-mutated human α-synuclein into the substantia nigra of rats, and evaluated them 1, 2, 4 and 16 weeks post-inoculation by immunohistochemistry and immunofluorescence to study degeneration and distribution of α-synuclein in the midbrain and hippocampus. The object location test was used to evaluate hippocampal-dependent memory. Sequential window acquisition of all theoretical mass spectrometry-based proteomics and fluorescence analysis of single-synapse long-term potentiation were used to study alterations to protein composition and plasticity in isolated hippocampal synapses. The effect of L-DOPA and pramipexole on long-term potentiation was also tested. Human α-synuclein was found within dopaminergic and glutamatergic neurons of the ventral tegmental area, and in dopaminergic, glutamatergic and GABAergic axon terminals in the hippocampus from 1 week post-inoculation, concomitant with mild dopaminergic degeneration in the ventral tegmental area. In the hippocampus, differential expression of proteins involved in synaptic vesicle cycling, neurotransmitter release and receptor trafficking, together with impaired long-term potentiation were the first events observed (1 week post-inoculation), preceding cognitive deficits (4 weeks post-inoculation). Later on, at 16 weeks post-inoculation, there was a deregulation of proteins involved in synaptic function, particularly those involved in the regulation of membrane potential, ion balance and receptor signalling. Hippocampal long-term potentiation was impaired before and soon after the onset of cognitive deficits, at 1 and 4 weeks post-inoculation, respectively. L-DOPA recovered hippocampal long-term potentiation more efficiently at 4 weeks post-inoculation than pramipexole, which partially rescued it at both time points. Overall, we found impaired synaptic plasticity and proteome dysregulation at hippocampal terminals to be the first events that contribute to the development of cognitive deficits in experimental parkinsonism. Our results not only point to dopaminergic but also to glutamatergic and GABAergic dysfunction, highlighting the relevance of the three neurotransmitter systems in the ventral tegmental area-hippocampus interaction from the earliest stages of parkinsonism. The proteins identified in the current work may constitute potential biomarkers of early synaptic damage in the hippocampus and hence, therapies targeting these could potentially restore early synaptic malfunction and consequently, cognitive deficits in Parkinson's disease.

The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain.

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20-99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF-activated transcription factor, cyclic-AMP response element-binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain.

Chemical-analytical characterization and leaching of heavy metals associated with nanoparticles and microplastics from commercial face masks and the abundance of personal protective equipment (PPE) waste in three metropolitan cities of South America.

In this study, we surveyed the presence of personal protective equipment (PPE) waste on the streets of Bogotá-Colombia, Lima-Perú, and Mar del Plata-Argentina. Furthermore, this work is also focused on the release capacity of Ag, Cu, and Zn metals associated with nanoparticles, and microplastics (MPs) from textile face masks (TFMs) and disposable face masks. According to our results, an association between low-income areas and PPE waste was found, which may be related to the periodicity of waste collection and economic activity. Polymers, like polypropylene, cotton-polyester, and additives, such as CaCO3, MgO, and Ag/Cu as nanoparticles, were identified. TFMs released high levels of Cu (35,900-60,200 µg·L-1), Zn (2340-2380 µg·L-1), and MPs (4528-10,640 particles/piece). Metals associated with nanoparticles leached by face masks did not present any antimicrobial activity against P. aeruginosa. Our study suggests that TFMs may leach large amounts of polluting nano/micromaterials in aquatic environments with potential toxicological effects on organisms.

European Association of Urology biochemical recurrence risk groups after radical prostatectomy: External validation and identification of independent risk factors for progression and death.

BACKGROUND: The EAU proposed a progression and death risk classification in patients with biochemical recurrence after radical prostatectomy (PR). OBJECTIVE: To validate the EAU BCR-risk classification in our setting and to find factors related to progression and death. MATERIAL AND METHODS: Multicenter, retrospective, observational study including 2140 patients underwent RP between 2011 and 2015. Patients with BCR were identified and stratified in low risk (PSA-DT >1yr and pGS <8) or high-risk (PSA-DT ≤1yr or pGS ≥8) grouping. PSA and metastatic free survival (PSA-PFS, MFS), cancer specific survival (CSS) and overall survival (OS) were calculated (Kaplan Meier curves and log-rank test). Independent risk factors were identified (Cox regression). RESULTS: 427 patients experienced BCR (32.3% low-risk and 67.7% high-risk). Median PSA-PFS was 135,0 mo (95% CI 129,63-140,94) and 115,0 mo (95% CI 104,02-125,98) (p<0,001), for low and high-risk groups, respectively. There were also significant differences in MFS and OS. The EAU BCR risk grouping was independent factor for PSA-progression (HR 2.55, p 0.009). Time from PR to BCR, was an independent factor for metastasis onset (HR 0.43, 95% CI 0.18-0.99; p 0.044) and death (HR 0.17, 95% CI 0.26.0.96; 23 p 0.048). Differences in MFS (p 0.001) and CSS (p 0.004) were found for <12, ≥12-<36 and ≥36 months from PR to BCR. Others independent factors were early salvage radiotherapy and PSA at BCR. CONCLUSIONS: High-risk group is a prognostic factor for biochemical progression, but it has a limited accuracy on MP and death in our setting. The inclusion of other factors could increase its predictive power.

Hybrid Methacrylated Gelatin and Hyaluronic Acid Hydrogel Scaffolds. Preparation and Systematic Characterization for Prospective Tissue Engineering Applications.

Hyaluronic acid (HA) and gelatin (Gel) are major components of the extracellular matrix of different tissues, and thus are largely appealing for the construction of hybrid hydrogels to combine the favorable characteristics of each biopolymer, such as the gel adhesiveness of Gel and the better mechanical strength of HA, respectively. However, despite previous studies conducted so far, the relationship between composition and scaffold structure and physico-chemical properties has not been completely and systematically established. In this work, pure and hybrid hydrogels of methacroyl-modified HA (HAMA) and Gel (GelMA) were prepared by UV photopolymerization and an extensive characterization was done to elucidate such correlations. Methacrylation degrees of ca. 40% and 11% for GelMA and HAMA, respectively, were obtained, which allows to improve the hydrogels' mechanical properties. Hybrid GelMA/HAMA hydrogels were stiffer, with elastic modulus up to ca. 30 kPa, and porous (up to 91%) compared with pure GelMA ones at similar GelMA concentrations thanks to the interaction between HAMA and GelMA chains in the polymeric matrix. The progressive presence of HAMA gave rise to scaffolds with more disorganized, stiffer, and less porous structures owing to the net increase of mass in the hydrogel compositions. HAMA also made hybrid hydrogels more swellable and resistant to collagenase biodegradation. Hence, the suitable choice of polymeric composition allows to regulate the hydrogels´ physical properties to look for the most optimal characteristics required for the intended tissue engineering application.

Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.

The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.

Intra- and extracellular ß-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus.

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as ß-amyloid (Aß) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aß either intra or extracellularly. We observed that expression of Aß in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aß inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aß in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aß oligomers both in vivo and in vitro.

Combination of light-driven co-delivery of chemodrugs and plasmonic-induced heat for cancer therapeutics using hybrid protein nanocapsules.

BACKGROUND: Improving the water solubility of hydrophobic drugs, increasing their accumulation in tumor tissue and allowing their simultaneous action by different pathways are essential issues for a successful chemotherapeutic activity in cancer treatment. Considering potential clinical application in the future, it will be promising to achieve such purposes by developing new biocompatible hybrid nanocarriers with multimodal therapeutic activity. RESULTS: We designed and characterised a hybrid nanocarrier based on human serum albumin/chitosan nanoparticles (HSA/chitosan NPs) able to encapsulate free docetaxel (DTX) and doxorubicin-modified gold nanorods (DOXO-GNRs) to simultaneously exploit the complementary chemotherapeutic activities of both antineoplasic compounds together with the plasmonic optical properties of the embedded GNRs for plasmonic-based photothermal therapy (PPTT). DOXO was assembled onto GNR surfaces following a layer-by-layer (LbL) coating strategy, which allowed to partially control its release quasi-independently release regarding DTX under the use of near infrared (NIR)-light laser stimulation of GNRs. In vitro cytotoxicity experiments using triple negative breast MDA-MB-231 cancer cells showed that the developed dual drug encapsulation approach produces a strong synergistic toxic effect to tumoral cells compared to the administration of the combined free drugs; additionally, PPTT enhances the cytostatic efficacy allowing cell toxicities close to 90% after a single low irradiation dose and keeping apoptosis as the main cell death mechanism. CONCLUSIONS: This work demonstrates that by means of a rational design, a single hybrid nanoconstruct can simultaneously supply complementary therapeutic strategies to treat tumors and, in particular, metastatic breast cancers with good results making use of its stimuli-responsiveness as well as its inherent physico-chemical properties.

Hippocampal gene expression patterns linked to late-life physical activity oppose age and AD-related transcriptional decline.

Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 years), cognitively intact aging (73-95 years) and age-matched AD cases. To identify "anti-aging/AD" transcription patterns associated with physical activity, probesets significantly associated with both physical activity and aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2210 probesets significant in both data sets, nearly 95% showed opposite transcription patterns with physical activity compared with aging/AD. The majority (>70%) of these anti-aging/AD genes showed increased expression with physical activity and decreased expression in aging/AD. Enrichment analysis of the anti-aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling, and spine plasticity. Anti-aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function (notably negative regulation of transcription). These data reveal that physical activity is associated with a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

Inhibition of LTP-Induced Translation by IL-1ß Reduces the Level of Newly Synthesized Proteins in Hippocampal Dendrites.

In rodent hippocampus, the inflammatory cytokine interleukin-1ß (IL-1ß) impairs memory and long-term potentiation (LTP), a major form of plasticity that depends on protein synthesis. A better understanding of the mechanisms by which IL-1ß impairs LTP may help identify targets for preventing cognitive deterioration. We tested whether IL-1ß inhibits protein synthesis in hippocampal neuron cultures following chemically induced LTP (cLTP). Fluorescent-tagging using click-chemistry showed that IL-1ß reduces the level of newly synthesized proteins in proximal dendrites of cLTP stimulated neurons. Relative to controls, in cLTP stimulated neurons, IL-1ß inhibited Akt/mTOR signaling, as well as the upregulation of GluA1, an AMPA receptor subunit, and LIMK1, a kinase that promotes actin polymerization. Notably, a novel TIR domain peptidomimetic (EM163) blocked both the activation of p38 and the suppression of cLTP-dependent protein synthesis by IL-1ß. Our data support a model where IL-1ß suppresses LTP directly in neurons by inhibiting mTOR-dependent translation.

TNFα and IL-1ß but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse.

CNS inflammatory responses are linked to cognitive impairment in humans. Research in animal models supports this connection by showing that inflammatory cytokines suppress long-term potentiation (LTP), the best-known cellular correlate of memory. Cytokine-induced modulation of LTP has been previously studied in vivo or in brain slices, two experimental approaches containing multiple cell populations responsive to cytokines. In their target cells, cytokines commonly increase the expression of multiple cytokines, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Whether cytokines suppress LTP by direct effects on neurons or by indirect mechanisms is still an open question. Here, we evaluated the effect of a major set of inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) on chemically-induced LTP (cLTP) in isolated hippocampal synaptosomes of mice, using fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). We found that TNFα and IL-1ß suppress synaptosomal cLTP. In contrast, cLTP was not affected by IL-18, at a concentration previously shown to block LTP in hippocampal slices. We also found that IL-18 does not impair cLTP or brain-derived neurotrophic factor (BDNF) signaling in primary hippocampal neuronal cultures. Thus, using both synaptosomes and neuron cultures, our data suggest that IL-18 impairs LTP by indirect mechanisms, which may depend on non-neuronal cells, such as glia. Notably, our results demonstrate that TNFα and IL-1ß directly suppress hippocampal plasticity via neuron-specific mechanisms. A better understanding of the brain's cytokine networks and their final molecular effectors is crucial to identify specific targets for intervention.

IL-1ß suppresses cLTP-induced surface expression of GluA1 and actin polymerization via ceramide-mediated Src activation.

BACKGROUND: Brain inflammation including increases in inflammatory cytokines such as IL-1ß is widely believed to contribute to the pathophysiology of Alzheimer's disease. Although IL-1ß-induced impairments in long-term potentiation (LTP) in acute hippocampal slices and memory functions in vivo have been well documented, the neuron-specific molecular mechanisms of IL-1ß-mediated impairments of LTP and memory remain unclear. METHODS: This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1ß on chemical LTP (cLTP)-induced structural plasticity and signaling. RESULTS: We found that IL-1ß reduces both the surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 and the spine growth following cLTP. These effects of IL-1ß were mediated by impairing actin polymerization during cLTP, as IL-1ß decreased the cLTP-induced formation of F-actin, and the effect of IL-1ß on cLTP-induced surface expression of GluA1 can be mimicked by latrunculin, a toxin that disrupts dynamics of actin filaments, and can be prevented by jasplakinolide, a cell-permeable peptide that stabilizes F-actin. Moreover, live-cell imaging demonstrated that IL-1ß decreased the stability of the actin cytoskeleton in spines, which is required for LTP consolidation. We further examined the role of sphingolipid signaling in the IL-1ß-mediated impairment of spine plasticity and found that both the neutral sphingomyelinase inhibitor GW4869 and the inhibitor of Src kinase PP2 attenuated the IL-1ß-mediated suppression of cLTP-induced surface expression of GluA1 and actin polymerization. CONCLUSIONS: These findings support a mechanism by which IL-1ß, via the sphingomyelinase/ceramide/Src pathway, impairs structural spine remodeling essential for LTP consolidation and memory.

On the road towards the global analysis of human synapses.

Synapses are essential units for the flow of information in the brain. Over the last 70 years, synapses have been widely studied in multiple animal models including worms, fruit flies, and rodents. In comparison, the study of human synapses has evolved significantly slower, mainly because of technical limitations. However, three novel methods allowing the analysis of molecular, morphological, and functional properties of human synapses may expand our knowledge of the human brain. Here, we briefly describe these methods, and evaluate how the information provided by each unique approach may contribute to the functional and anatomical analysis of the synaptic component of human brain circuitries. In particular, using tissue from cryopreserved human brains, synaptic plasticity can be studied in isolated synaptosomes by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP), and subpopulations of synapses can be thoroughly assessed in the ribbons of brain tissue by array tomography (AT). Currently, it is also possible to quantify synaptic density in the living human brain by positron emission tomography (PET), using a novel synaptic radio-ligand. Overall, data provided by FASS-LTP, AT, and PET may significantly contribute to the global understanding of synaptic structure and function in both healthy and diseased human brains, thus directly impacting translational research.

Early spectra of the gravitational wave source GW170817: Evolution of a neutron star merger.

On 17 August 2017, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of SSS17a from 11.75 hours until 8.5 days after the merger. Over the first hour of observations, the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measured the photosphere cooling from [Formula: see text] to [Formula: see text] kelvin, and determined a photospheric velocity of roughly 30% of the speed of light. The spectra of SSS17a began displaying broad features after 1.46 days and evolved qualitatively over each subsequent day, with distinct blue (early-time) and red (late-time) components. The late-time component is consistent with theoretical models of r-process-enriched neutron star ejecta, whereas the blue component requires high-velocity, lanthanide-free material.

Abnormalities of Dopamine D3 Receptor Signaling in the Diseased Brain.

Dopamine D3 receptors (D3R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D3R signaling contributes to multiple brain diseases, such as Parkinson's disease, essential tremor, schizophrenia, and addiction. In line with these findings, D3R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D3R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D3R signaling via monomeric D3R and heteromeric receptor complexes (e.g., D3R-D1R, D3R-D2R, D3R-A2aR, and D3R-D3nf). I focus on D3R signaling pathways that, according to recent reports, contribute to pathological brain states. In particular, I describe evidence on both quantitative (e.g., increased number or affinity) and qualitative (e.g., switched signaling) changes in D3R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D3R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D3R signaling. Because several lines of evidence support the idea that imbalances in D3R signaling alter neural function, a better understanding of downstream D3R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders.

Cytokines and cytokine networks target neurons to modulate long-term potentiation.

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines.

IL-1ß impairs retrograde flow of BDNF signaling by attenuating endosome trafficking.

BACKGROUND: Pro-inflammatory cytokines accumulate in the brain with age and Alzheimer's disease and can impair neuron health and cognitive function. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin that supports neuron health, function, and synaptic plasticity. The pro-inflammatory cytokine interleukin-1ß (IL-1ß) impairs BDNF signaling but whether it affects BDNF signaling endosome trafficking has not been studied. METHODS: This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1ß on BDNF signaling endosome trafficking. Neurons were cultured in microfluidic chambers that separate the environments of the cell body and its axon terminal, enabling us to specifically treat in axon compartments and trace vesicle trafficking in real-time. RESULTS: We found that IL-1ß attenuates BDNF signaling endosomes throughout networks in cultures. In IL-1ß-treated cells, overall BDNF endosomal density was decreased, and the colocalization of BDNF endosomes with presynaptic terminals was found to be more than two times higher than in control cultures. Selective IL-1ß treatment to the presynaptic compartment in microfluidic chamber attenuated BDNF endosome flux, as measured by reduced BDNF-GFP endosome counts in the somal compartment. Further, IL-1ß decreased the BDNF-induced phosphorylation of Erk5, a known BDNF retrograde trafficking target. Mechanistically, the deficiency in trafficking was not due to impaired endocytosis of the BDNF-TrkB complex, or impaired transport rate, since BDNF endosomes traveled at the same rate in both control and IL-1ß treatment groups. Among the regulators of presynaptic endosome sorting is the post-translational modification, ubiquitination. In support of this possibility, the IL-1ß-mediated suppression of BDNF-induced Erk5 phosphorylation can be rescued by exogenous ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that regulates ubiquitin and endosomal trafficking. CONCLUSIONS: We observed a state of neurotrophic resistance whereby, in the prolonged presence of IL-1ß, BDNF is not effective in delivering long-distance signaling via the retrograde transport of signaling endosomes. Since IL-1ß accumulation is an invariant feature across many neurodegenerative diseases, our study suggest that compromised BDNF retrograde transport-dependent signaling may have important implications in neurodegenerative diseases.