The role of the Toll like receptor 4 signaling in sex-specific persistency of depression-like behavior in response to chronic stress.

Chronic stress is a major risk factor for Major Depressive Disorder (MDD), and it has been shown to impact the immune system and cause microglia activation in the medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. The aim of this study is to further investigate cellular and molecular mechanisms underlying persistent depression behavior in sex specific manner, which is observed clinically. Here, we report that both male and female mice exhibited depression-like behavior following exposure to chronic stress. However, only female mice showed persistent depression-like behavior, which was associated with microglia activation in mPFC, characterized by distinctive alterations in the phenotype of microglia. Given these findings, to further investigate the underlying molecular mechanisms associated with persistent depression-like behavior and microglia activation in female mice, we used translating-ribosome affinity purification (TRAP). We find that Toll like receptor 4 (TLR4) signaling is casually related to persistent depression-like behavior in female mice. This is supported by the evidence that the fact that genetic ablation of TLR4 expression in microglia significantly reduced the persistent depression-like behavior to baseline levels in female mice. This study tentatively supports the hypothesis that the TLR4 signaling in microglia may be responsible for the sex differences in persistent depression-like behavior in female.

Targeting insulin-like growth factor-1 receptor (IGF1R) for brain delivery of biologics.

The blood-brain barrier (BBB) prevents the majority of drugs from crossing into the brain and reaching neurons. To overcome this challenge, safe and non-invasive technologies targeting receptor-mediated pathways have been developed. In this study, three single-domain antibodies (sdAbs; IGF1R3, IGF1R4, and IGF1R5) targeting the extracellular domain of the human insulin-like growth factor-1 receptor (IGF1R), generated by llama immunization, showed enhanced transmigration across the rat BBB model (SV-ARBEC) in vitro. The rate of brain uptake of these sdAbs fused to mouse Fc (sdAb-mFc) in vivo was estimated using the fluorescent in situ brain perfusion (ISBP) technique followed by optical brain imaging and distribution volume evaluation. Compared to the brains perfused with the negative control A20.1-mFc, the brains perfused with anti-IGF1R sdAbs showed a significant increase of the total fluorescence intensity (~2-fold, p < .01) and the distribution volume (~4-fold, p < .01). The concentration curve for IGF1R4-mFc demonstrated a linear accumulation plateauing at approximately 400 µg (~1 µM), suggesting a saturable mechanism of transport. Capillary depletion and mass spectrometry analyses of brain parenchyma post-ISBP confirmed the IGF1R4-mFc brain uptake with ~25% of the total amount being accumulated in the parenchymal fraction in contrast to undetectable levels of A20.1-mFc after a 5-min perfusion protocol. Systemic administration of IGF1R4-mFc fused with the non-BBB crossing analgesic peptide galanin (2 and 5 mg/kg) induced a dose-dependent suppression of thermal hyperalgesia in the Hargreaves pain model. In conclusion, novel anti-IGF1R sdAbs showed receptor-mediated brain uptake with pharmacologically effective parenchymal delivery of non-permeable neuroactive peptides.

Impact of an NCCN-Compliant Multidisciplinary Conference on Treatment Decisions for Localized Prostate Cancer.

BACKGROUND: We sought to investigate the impact of an NCCN-compliant multidisciplinary conference on treatment decisions of patients with localized prostate cancer. METHODS: A retrospective review of our quality assurance localized prostate cancer database was performed. All patients with localized prostate cancer who sought a second opinion at Roswell Park Comprehensive Cancer Center between 2009 and 2019 were presented to the multidisciplinary Localized Prostate Cancer Conference (LPCC) that includes urologists, radiation oncologists, pathologists, and patient advocates. Multivariable regression models were fit to evaluate variables associated with concordance between community recommendations, LPCC recommendations, and treatment received by patients. RESULTS: A total of 1,164 patients were identified, of whom 26% had NCCN very low-/low-risk, 27% had favorable intermediate-risk, 25% had unfavorable intermediate-risk, and 22% had high-/very high-risk prostate cancer. Pathology changed in 11% of patients after genitourinary pathologist review, which caused disease reclassification in 9%. Concordance between community and LPCC recommendations occurred in 78%, with lowest concordance for androgen deprivation therapy (21%) and radiotherapy (53%). Concordance between community recommendations and treatment received occurred in 65%, with lowest concordance for androgen deprivation therapy and radiotherapy; among those who were recommended radiotherapy as the only option by their community urologist, only 26% received it. Concordance between LPCC recommendations and treatment received occurred in 92%. CONCLUSIONS: Community recommendations differed from the multidisciplinary NCCN-compliant recommendations in 22% of patients, primarily for radiotherapy. Multidisciplinary recommendations matched the treatment received in 92% of patients compared with 65% for community recommendations.

The Implementation of Precise Point Positioning (PPP): A Comprehensive Review.

High-precision positioning from Global Navigation Satellite Systems (GNSS) has garnered increased interest due to growing demand in various applications, like autonomous car navigation and precision agriculture. Precise Point Positioning (PPP) offers a distinct advantage over differential techniques by enabling precise position determination of a GNSS rover receiver through the use of external corrections sourced from either the Internet or dedicated correction satellites. However, PPP's implementation has been challenging due to the need to mitigate numerous GNSS error sources, many of which are eliminated in differential techniques such as Real-Time Kinematics (RTK) or overlooked in Standard Point Positioning (SPP). This paper extensively reviews PPP's error sources, such as ionospheric delays, tropospheric delays, satellite orbit and clock errors, phase and code biases, and site displacement effects. Additionally, this article examines various PPP models and correction sources that can be employed to address these errors. A detailed discussion is provided on implementing the standard dual-frequency (DF)-PPP to achieve centimeter- or millimeter-level positioning accuracy. This paper includes experimental examples of PPP implementation results using static data from the International GNSS Service (IGS) station network and a kinematic road test based on the actual trajectory to showcase DF-PPP development for practical applications. By providing a fusion of theoretical insights with practical demonstrations, this comprehensive review offers readers a pragmatic perspective on the evolving field of Precise Point Positioning.

Real-Time Safe Landing Zone Identification Based on Airborne LiDAR.

Over the past two decades, there has been a growing demand for generating digital surface models (DSMs) in real-time, particularly for aircraft landing in degraded visual environments. Challenging landing environments can hinder a pilot's ability to accurately navigate, see the ground, and avoid obstacles that may lead to equipment damage or loss of life. While many accurate and robust filtering algorithms for airborne laser scanning (ALS) data have been developed, they are typically computationally expensive. Moreover, these filtering algorithms require high execution times, making them unsuitable for real-time applications. This research aims to design and implement an efficient algorithm that can be used in real-time on limited-resource embedded processors without the need for a supercomputer. The proposed algorithm effectively identifies the best safe landing zone (SLZ) for an aircraft/helicopter based on processing 3D LiDAR point cloud data collected from a LiDAR mounted on the aircraft/helicopter. The algorithm was successfully implemented in C++ in real-time and validated using professional software for flight simulation. By comparing the results with maps, this research demonstrates the ability of the developed method to assist pilots in identifying the safest landing zone for helicopters.

Ileal conduit versus neobladder: A propensity score-matched analysis of the effect on renal function.

OBJECTIVES: To analyze the long-term effects of continent (neobladder) compared with incontinent (ileal conduit) urinary diversion. METHODS: We carried out a retrospective review of our departmental database. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Neobladder and ileal conduit patients were matched in a 1:2 ratio and a propensity score-matched analysis was carried out. Data were summarized using descriptive analysis. Trend plots were generated using baseline and follow-up creatinine values to compare estimated glomerular filtration rate at 3 months, then annually for 5 years. Variables associated with estimated glomerular filtration rate were assessed using multivariate linear analysis. RESULTS: Our cohort consisted of 137 patients (neobladder n = 50 and ileal conduit n = 87) with a median follow-up time of 3 years (interquartile range 1-7 years). The ileal conduit group had shorter operative times (352 vs 444 min, P < 0.01), intracorporeal diversions were more common (66% vs 44%, P = 0.01), had prior abdominal surgery (66% vs 38%, P < 0.01) and had radiation (9% vs 0%, P = 0.03). The neobladder group more commonly had recurrent urinary tract infections (22% vs 3%, P < 0.01) and a steeper decrease in estimated glomerular filtration rate in the first year. On multivariate linear analysis, age/year (-0.59), body mass index per kg/m2 (-0.52), preoperative estimated glomerular filtration rate per unit (0.51), recurrent urinary tract infections (-14.03) and time versus day 90 (year 1, -7.52; year 2, -9.06; year 3, -10.78) were significantly associated with estimated glomerular filtration rate. CONCLUSION: Ileal conduits and neobladders showed a similar effect on the estimated glomerular filtration rate up to 5 years after robot-assisted radical cystectomy. Recurrent urinary tract infections were associated with a worse estimated glomerular filtration rate.

Correction: Elsheikh et al. Low-Cost Real-Time PPP/INS Integration for Automated Land Vehicles. Sensors 2019, 19, 4896.

The authors wish to make the following corrections in the original paper [...].

Functional outcomes after robot-assisted radical cystectomy: A review of literature.

Robot-assisted radical cystectomy has steadily gained wider acceptance among urologists compared with open and laparoscopic approaches. Robot-assisted radical cystectomy has shown comparable perioperative and oncologic outcomes compared with open radical cystectomy. Nevertheless, data about the functional outcomes and quality of life after robot-assisted radical cystectomy remain limited. We sought to review the literature and describe urinary, sexual and bowel functions after robot-assisted radical cystectomy in addition to mental health and health-related quality of life. Despite limitations of the available literature, data suggests that functional outcomes after robot-assisted radical cystectomy are comparable to open radical cystectomy. However, more studies utilizing standardized definitions are required.

Surgical Hand Gesture Recognition Utilizing Electroencephalogram as Input to the Machine Learning and Network Neuroscience Algorithms.

Surgical gestures detection can provide targeted, automated surgical skill assessment and feedback during surgical training for robot-assisted surgery (RAS). Several sources including surgical videos, robot tool kinematics, and an electromyogram (EMG) have been proposed to reach this goal. We aimed to extract features from electroencephalogram (EEG) data and use them in machine learning algorithms to classify robot-assisted surgical gestures. EEG was collected from five RAS surgeons with varying experience while performing 34 robot-assisted radical prostatectomies over the course of three years. Eight dominant hand and six non-dominant hand gesture types were extracted and synchronized with associated EEG data. Network neuroscience algorithms were utilized to extract functional brain network and power spectral density features. Sixty extracted features were used as input to machine learning algorithms to classify gesture types. The analysis of variance (ANOVA) F-value statistical method was used for feature selection and 10-fold cross-validation was used to validate the proposed method. The proposed feature set used in the extra trees (ET) algorithm classified eight gesture types performed by the dominant hand of five RAS surgeons with an accuracy of 90%, precision: 90%, sensitivity: 88%, and also classified six gesture types performed by the non-dominant hand with an accuracy of 93%, precision: 94%, sensitivity: 94%.

The Use of Antimicrobial and Antiviral Drugs in Alzheimer's Disease.

The aggregation and accumulation of amyloid-ß plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer's disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-ß peptides being limited at best, a greater understanding of the physiological role of amyloid-ß peptides is needed. The development of amyloid-ß plaques has been determined to occur 10-20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-ß peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-ß plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-ß, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer's disease.

Low-Cost Real-Time PPP/INS Integration for Automated Land Vehicles.

The last decade has witnessed a growing demand for precise positioning in many applications including car navigation. Navigating automated land vehicles requires at least sub-meter level positioning accuracy with the lowest possible cost. The Global Navigation Satellite System (GNSS) Single-Frequency Precise Point Positioning (SF-PPP) is capable of achieving sub-meter level accuracy in benign GNSS conditions using low-cost GNSS receivers. However, SF-PPP alone cannot be employed for land vehicles due to frequent signal degradation and blockage. In this paper, real-time SF-PPP is integrated with a low-cost consumer-grade Inertial Navigation System (INS) to provide a continuous and precise navigation solution. The PPP accuracy and the applied estimation algorithm contributed to reducing the effects of INS errors. The system was evaluated through two road tests which included open-sky, suburban, momentary outages, and complete GNSS outage conditions. The results showed that the developed PPP/INS system maintained horizontal sub-meter Root Mean Square (RMS) accuracy in open-sky and suburban environments. Moreover, the PPP/INS system could provide a continuous real-time positioning solution within the lane the vehicle is moving in. This lane-level accuracy was preserved even when passing under bridges and overpasses on the road. The developed PPP/INS system is expected to benefit low-cost precise land vehicle navigation applications including level 2 of vehicle automation which comprises services such as lane departure warning and lane-keeping assistance.

In vitro evaluation of archaeosome vehicles for transdermal vaccine delivery.

Archaeosomes composed of archaeal total polar lipids (TPL) or semi-synthetic analog vesicles have been used as vaccine adjuvants and delivery systems in animal models for many years. Typically administered by intramuscular or subcutaneous injections, archaeosomes can induce robust, long-lasting humoral and cell-mediated immune responses against entrapped antigens and provide protection in murine models of infectious disease and cancer. Herein, we evaluated various archaeosomes for transdermal delivery, since this route may help eliminate needle-stick injuries and needle re-use, and therefore increase patient compliance. Archaeosomes composed of TPL from different archaea (Halobacterium salinarum, Methanobrevibacter smithii, Haloferax volcanii) and various semi-synthetic glycolipid combinations were evaluated for their ability to diffuse across the skin barrier using an ex vivo pig skin model and the results were compared to conventional synthetic ester liposomes. Physicochemical characteristics were determined for selected formulations including vesicle size, size distribution, zeta potential, fluidity, antigen (ovalbumin) incorporation efficiency and release. Archaeosomes, in particular those composed of M. smithii TPL or the synthetic glycolipid sulfated S-lactosylarchaeol (SLA) mixed with uncharged glycolipid lactosyl archaeol (LA), appeared to be effective carriers for ovalbumin, achieving much better antigen distribution and vesicle accumulation in the skin epidermis than conventional liposomes. The enhanced skin permeation of archaeosomes may be attributed to their chemical structure and physicochemical properties such as particle size, surface charge, stability, and fluidity of their lipid bilayer.

Research on an Improved Method for Foot-Mounted Inertial/Magnetometer Pedestrian-Positioning Based on the Adaptive Gradient Descent Algorithm.

Foot-mounted Inertial Pedestrian-Positioning Systems (FIPPSs) based on Micro Inertial Measurement Units (MIMUs), have recently attracted widespread attention with the rapid development of MIMUs. The can be used in challenging environments such as firefighting and the military, even without augmenting with Global Navigation Satellite System (GNSS). Zero Velocity Update (ZUPT) provides a solution for the accumulated positioning errors produced by the low precision and high noise of the MIMU, however, there are some problems using ZUPT for FIPPS, include fast-initial alignment and unobserved heading misalignment angle, which are addressed in this paper. Our first contribution is proposing a fast-initial alignment algorithm for foot-mounted inertial/magnetometer pedestrian positioning based on the Adaptive Gradient Descent Algorithm (AGDA). Considering the characteristics of gravity and Earth's magnetic field, measured by accelerometers and magnetometers, respectively, when the pedestrian is standing at one place, the AGDA is introduced as the fast-initial alignment. The AGDA is able to estimate the initial attitude and enhance the ability of magnetic disturbance suppression. Our second contribution in this paper is proposing an inertial/magnetometer positioning algorithm based on an adaptive Kalman filter to solve the problem of the unobserved heading misalignment angle. The algorithm utilizes heading misalignment angle as an observation for the Kalman filter and can improve the accuracy of pedestrian position by compensating for magnetic disturbances. In addition, introducing an adaptive parameter in the Kalman filter is able to compensate the varying magnetic disturbance for each ZUPT instant during the walking phase of the pedestrian. The performance of the proposed method is examined by conducting pedestrian test trajectory using MTi-G710 manufacture by XSENS. The experimental results verify the effectiveness and applicability of the proposed method.

Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes.

The posttranslational modification of therapeutic proteins with terminal sialic acids is one means of improving their circulating half-life, thereby improving their efficiency. We have developed a two-step in vitro enzymatic modification of glycoproteins, which has previously only been achieved by chemical means [Gregoriadis G, Jain S, Papaioannou I, Laing P (2005) Int J Pharm 300:125-130). This two-step procedure uses the Campylobacter jejuni Cst-II α2,8-sialyltransferase to provide a primer on N-linked glycans, followed by polysialylation using the Neisseria meningitidis α2,8-polysialyltransferase. Here, we have demonstrated the ability of this system to modify three glycoproteins with varying N-linked glycan compositions: the human therapeutic proteins alpha-1-antitrypsin (A1AT) and factor IX, as well as bovine fetuin. The chain length of the polysialic acid addition was optimized by controlling reaction conditions. After demonstrating the ability of this system to modify a variety of proteins, the effect of polysialylation on the activity and serum half-life of A1AT was examined. The polysialylation of A1AT did not adversely affect its in vitro inhibition activity against human neutrophil elastase. The polysialylation of A1AT resulted in a significantly improved pharmacokinetic profile when the modified proteins were injected into CD-1 mice. Together, these results suggest that polysialylated A1AT may be useful for improved augmentation therapy for patients with a deficiency in this protein and that this modification may be applied to other therapeutic proteins.

Psychobiotics and the Microbiota-Gut-Brain Axis: Where Do We Go from Here?

The bidirectional relationship between the gut microbiota and the nervous system is known as the microbiota-gut-brain axis (MGBA). The MGBA controls the complex interactions between the brain, the enteric nervous system, the gut-associated immune system, and the enteric neuroendocrine systems, regulating key physiological functions such as the immune response, sleep, emotions and mood, food intake, and intestinal functions. Psychobiotics are considered tools with the potential to modulate the MGBA through preventive, adjunctive, or curative approaches, but their specific mechanisms of action on many aspects of health are yet to be characterized. This narrative review and perspectives article highlights the key paradigms needing attention as the scope of potential probiotics applications in human health increases, with a growing body of evidence supporting their systemic beneficial effects. However, there are many limitations to overcome before establishing the extent to which we can incorporate probiotics in the management of neuropsychiatric disorders. Although this article uses the term probiotics in a general manner, it remains important to study probiotics at the strain level in most cases.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

Comparison of T2 and T2*-weighted MR molecular imaging of a mouse model of glioma.

BACKGROUND: Standard MRI has been used for high-grade gliomas detection, albeit with limited success as it does not provide sufficient specificity and sensitivity to detect complex tumor structure. Therefore targeted contrast agents based on iron oxide, that shorten mostly T2 relaxation time, have been recently applied. However pulse sequences for molecular imaging in animal models of gliomas have not been yet fully studied. The aim of this study was therefore to compare contrast-to-noise ratio (CNR) and explain its origin using spin-echo (SE), gradient echo (GE), GE with flow compensation (GEFC) as well as susceptibility weighted imaging (SWI) in T2 and T2* contrast-enhanced molecular MRI of glioma. METHODS: A mouse model was used. U87MGdEGFRvIII cells (U87MG), derived from a human tumor, were injected intracerebrally. A 9.4 T MRI system was used and MR imaging was performed on the 10 day after the inoculation of the tumor. The CNR was measured prior, 20 min, 2 hrs and 24 hrs post intravenous tail administration of glioma targeted paramagnetic nanoparticles (NPs) using SE, SWI, GE and GEFC pulse sequences. RESULTS: The results showed significant differences in CNR among all pulse sequences prior injection. GEFC provided higher CNR post contrast agent injection when compared to GE and SE. Post injection CNR was the highest with SWI and significantly different from any other pulse sequence. CONCLUSIONS: Molecular MR imaging using targeted contrast agents can enhance the detection of glioma cells at 9.4 T if the optimal pulse sequence is used. Hence, the use of flow compensated pulse sequences, beside SWI, should to be considered in the molecular imaging studies.

The Bioactive Dietary Polyphenol Preparation Alleviates Depression and Anxiety-Like Behaviors by Modulating the Regional Heterogeneity of Microglia Morphology.

SCOPE: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. METHODS AND RESULTS: The study finds that treatment with BDPP significantly decreases depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. The study also finds that BDPP treatment reverses microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. CONCLUSION: The findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway may provide a new avenue for preventing the manifestation of psychiatric impairments including stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

The bioactive dietary polyphenol preparation alleviates depression and anxiety-like behaviors by modulating the regional heterogeneity of microglia morphology.

Scope: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. Methods and results: We find that treatment with BDPP significantly decreased depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. We also find that BDPP treatment reversed microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. Conclusion: Our findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway might provide a new avenue for therapeutic intervention in stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.