Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease.

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

Critical Care: What You May Have Missed in 2023.

Critical care medicine is a specialty that brings together a truly wide spectrum of patient populations, disease states, and treatment methods. This article highlights 10 important pieces of research from 2023 (and 1 from 2022) in critical care. The literature was screened for new evidence relevant to internal medicine physicians and hospitalists whose focus of practice is not critical care but who may be taking care of seriously ill patients. The articles highlight the diverse spectrum of pathology and interplay of various specialties that go into critical care. Topics include transfusion medicine, fluid resuscitation, safe intubation practices and respiratory failure, and the management of acute ischemic stroke. Several trials are groundbreaking, forcing clinicians to reconsider preexisting dogma and likely adopt new treatment strategies.

Pulmonology: What You May Have Missed in 2023.

The field of pulmonology saw significant advances in 2023. The publications highlighted in this article address advances and changes in practice related to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pleural disorders, and sleep-disordered breathing. One article reviews data examining the efficacy of vaccination against respiratory syncytial virus, a respiratory viral illness that has had devastating effects globally. Four studies evaluate the role of various therapies in COPD, including dupilumab, ensifentrine, pulmonary rehabilitation programs, and lung volume reduction versus endobronchial valves. Another study explores the effect on vascular events of positive-pressure ventilation in patients with sleep-disordered breathing and recent stroke. The use of combination therapy with rituximab and mycophenolate mofetil on progression-free survival in patients with nonspecific interstitial pneumonia is the topic of another study. We also highlight an update of clinical recommendations for the evaluation of patients with pleural disorders and a systematic review analyzing the effectiveness of inhaled corticosteroids as a supplement to dual therapy for COPD.

Transcriptomic Profiling Identifies CD8+ T Cells in the Brain of Aged and Alzheimer's Disease Transgenic Mice as Tissue-Resident Memory T Cells.

Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD progresses, CD8+ T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8+ T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8+ T cells in the brain, we explored and compared the transcriptomic profile of CD8+ T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8+ T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8+ T cells. The gene signature of brain CD8+ T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-ß signaling and the response to viral infections. Furthermore, brain CD8+ T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8+ T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8+ T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD.

Exploring PAH kinetics in wild vs. transplanted triploid and diploid oysters at a contaminated field site using immunological techniques.

Crassostrea virginica is a well-established bivalve species for biomonitoring persistent organic pollutants such as polycyclic aromatic hydrocarbons (PAH) in aquatic environments. Differing biomonitoring methods employing either wild oysters inhabiting sites of interest or naïve cultured oysters deployed to sites for extended periods can be used for site evaluations. However, important differences in total contaminant concentrations accumulated have been observed between the wild and transplanted groups. Furthermore, although rearing cultured triploid oysters is widely popular in commercial farming, the difference in contaminant bioaccumulation potential between triploid and diploid cultured oysters is vastly understudied, particularly for organic contaminants such as PAH. This study explores differences in PAH kinetics between transplanted triploid and diploid cultured oysters and wild oysters at a PAH-impacted site during a 6-week field exposure study using novel immunological techniques: antibody-based biosensor technology and immunofluorescence visualization. Conventional chemical analysis of oyster tissue was also conducted for comparison. While differences were observed in the oyster interstitial fluid between the wild and transplanted oysters throughout the study, whole tissue analysis revealed differing trends at each time point. Our findings suggest that insufficient equilibration time may contribute to the differences observed between groups. Furthermore, when combined with visual evidence via immunofluorescence, internal partitioning of contaminants may be an important determinant for total concentrations measured. A better understanding of the differences observed between wild and transplanted oyster groups is necessary for improved biomonitoring. Our study highlights the value in employing novel immunological techniques to explore possible mechanisms driving these differences.

Alternative intraoperative optical imaging modalities for fluorescence angiography in gastrointestinal surgery: spectral imaging and imaging photoplethysmography.

INTRODUCTION: Intraoperative near-infrared fluorescence angiography with indocyanine green (ICG-FA) is a well-established modality in gastrointestinal surgery. Its main drawback is the application of a fluorescent agent with possible side effects for patients. The goal of this review paper is the presentation of alternative, non-invasive optical imaging methods and their comparison with ICG-FA. MATERIAL AND METHODS: The principles of ICG-FA, spectral imaging, imaging photoplethysmography (iPPG), and their applications in gastrointestinal surgery are described based on selected published works. RESULTS: The main applications of the three modalities are the evaluation of tissue perfusion, the identification of risk structures, and tissue segmentation or classification. While the ICG-FA images are mainly evaluated visually, leading to subjective interpretations, quantitative physiological parameters and tissue segmentation are provided in spectral imaging and iPPG. The combination of ICG-FA and spectral imaging is a promising method. CONCLUSIONS: Non-invasive spectral imaging and iPPG have shown promising results in gastrointestinal surgery. They can overcome the main drawbacks of ICG-FA, i.e. the use of contrast agents, the lack of quantitative analysis, repeatability, and a difficult standardization of the acquisition. Further technical improvements and clinical evaluations are necessary to establish them in daily clinical routine.

Biosensor applications in contaminated estuaries: Implications for disaster research response.

BACKGROUND: Given the time and monetary costs associated with traditional analytical chemistry, there remains a need to rapidly characterize environmental samples for priority analysis, especially within disaster research response (DR2). As PAHs are both ubiquitous and occur as complex mixtures at many National Priority List sites, these compounds are of interest for post-disaster exposures. OBJECTIVE: This study tests the field application of the KinExA Inline Biosensor in Galveston Bay and the Houston Ship Channel (GB/HSC) and in the Elizabeth River, characterizing the PAH profiles of these region's soils and sediments. To our knowledge, this is the first application of the biosensor to include soils. METHODS: The biosensor enables calculation of total free PAHs in porewater (C free), which is confirmed through gas chromatography-mass spectrometry (GC-MS) analysis. To determine potential risk of the collected soils the United States Environmental Protection (USEPA) Agency's Regional Screening Level (RSL) Calculator is used along with the USEPA Region 4 Ecological Screening Values (R4-ESV) and Refined Screening Values (R4-RSV). RESULTS: Based on GC-MS results, all samples had PAH-related hazard indices below 1, indicating low noncarcinogenic risks, but some samples exceeded screening levels for PAH-associated cancer risks. Combining biosensor-based C free with Total Organic Carbon yields predictions highly correlated (r > 0.5) both with total PAH concentrations as well as with hazard indices and cancer risks. Additionally, several individual parent PAH concentrations in both the GB/HSC and Elizabeth River sediments exceeded the R4- ESV and R4-RSV values, indicating a need for follow-up sediment studies. CONCLUSIONS: The resulting data support the utility of the biosensor for future DR2 efforts to characterize PAH contamination, enabling preliminary PAH exposure risk screening to aid in prioritization of environmental sample analysis.

Focused ultrasound radiosensitizes human cancer cells by enhancement of DNA damage.

PURPOSE: High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40-47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT. METHODS: An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X­ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST­1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay). RESULTS: The FUS intensities of 213 (1.147 MHz) and 225 W/cm2 (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells. CONCLUSION: Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage.

Practical setting and potential applications of interventions guided by PET/MRI.

Multimodality imaging has emerged from a vision thirty years ago to routine clinical use today. Positron emission tomography (PET)/magnetic resonance imaging (MRI) is still relatively new in this arena and particularly suitable for clinical research and technical development. PET/MRI-guidance for interventions opens up opportunities for novel treatments but at the same time demands certain technical and organizational requirements to be fulfilled. In this work, we aimed to demonstrate a practical setting and potential application of PET/MRI guidance of interventional procedures. The superior quantitative physiologic information of PET, the various unique imaging characteristics of MRI, and the reduced radiation exposure are the most relevant advantages of this technique. As a noninvasive interventional tool, focused ultrasound (FUS) ablation of tumor cells would benefit from PET/MRI for diagnostics, treatment planning and intervention. Yet, technical limitations might impeed preclinical research, given that PET/MRI sites are per se not designed as interventional suites. Nonetheless, several approaches have been offered in the past years to upgrade MRI suites for interventional purposes. Taking advantage of state of the art and easy-to-use technology it is possible to create a supporting infrastructure that is suitable for broad preclinical adaption. Several aspects are to be addressed, including remote control of the imaging system, display of the imaging results, communication technology, and implementation of additional devices such as a FUS platform and an MR-compatible robotic system for positioning of the FUS equipment. Feasibility could be demostrated with an examplary experimental setup for interventional PET/MRI. Most PET/MRI sites could allow for interventions with just a few add-ons and modifications, such as comunication, in room image display and sytems control. By unlocking this feature, and driving preclinical research in interventional PET/MRI, translation of the protocol and methodology into clinical settings seems feasible.

The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice.

Alzheimer's disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling-more specifically, the leukotriene receptors-has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.

Inferring causal molecular networks: empirical assessment through a community-based effort.

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense.

Doublecortin expression in CD8+ T-cells and microglia at sites of amyloid-ß plaques: A potential role in shaping plaque pathology?

INTRODUCTION: One characteristic of Alzheimer's disease is the formation of amyloid-ß plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. METHODS: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid-ß plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. RESULTS: The plaque-associated DCX+ cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium-binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque-associated DCX+ cells was negative for ionized calcium-binding adapter molecule 1 but was highly positive for the pan-leukocyte marker CD45. These hematopoietic cells were identified as CD3-and CD8-positive and CD4-negative T-cells. DISCUSSION: Peculiarly, the DCX+/ionized calcium-binding adapter molecule 1+ microglia and DCX+/CD8+ T-cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology.

Scalable inference of heterogeneous reaction kinetics from pooled single-cell recordings.

Mathematical methods combined with measurements of single-cell dynamics provide a means to reconstruct intracellular processes that are only partly or indirectly accessible experimentally. To obtain reliable reconstructions, the pooling of measurements from several cells of a clonal population is mandatory. However, cell-to-cell variability originating from diverse sources poses computational challenges for such process reconstruction. We introduce a scalable Bayesian inference framework that properly accounts for population heterogeneity. The method allows inference of inaccessible molecular states and kinetic parameters; computation of Bayes factors for model selection; and dissection of intrinsic, extrinsic and technical noise. We show how additional single-cell readouts such as morphological features can be included in the analysis. We use the method to reconstruct the expression dynamics of a gene under an inducible promoter in yeast from time-lapse microscopy data.

Evaluation of a time efficient immunization strategy for anti-PAH antibody development.

The development of monoclonal antibodies (mAb) with affinity to small molecules can be a time-consuming process. To evaluate shortening the time for mAb production, we examined mouse antisera at different time points post-immunization to measure titer and to evaluate the affinity to the immunogen PBA (pyrene butyric acid). Fusions were also conducted temporally to evaluate antibody production success at various time periods. We produced anti-PBA antibodies 7 weeks post-immunization and selected for anti-PAH reactivity during the hybridoma screening process. Moreover, there were no obvious sensitivity differences relative to antibodies screened from a more traditional 18-week schedule. Our results demonstrate a more time efficient immunization strategy for anti-PAH antibody development that may be applied to other small molecules.

Monitoring of microvascular free flaps following oropharyngeal reconstruction using infrared thermography: first clinical experiences.

The aim of this study is to investigate static and dynamic infrared (IR) thermography for intra- and postoperative free-flap monitoring following oropharyngeal reconstruction. Sixteen patients with oropharyngeal reconstruction by free radial forearm flap were included in this prospective, clinical study (05/2013-08/2014). Prior ("intraop_pre") and following ("intraop_post") completion of the microvascular anastomoses, IR thermography was performed for intraoperative flap monitoring. Further IR images were acquired one day ("postop_1") and 10 days ("postop_10") after surgery for postoperative flap monitoring. Of the 16, 15 transferred free radial forearm flaps did not show any perfusion failure. A significant decreasing mean temperature difference (∆T: temperature difference between the flap surface and the surrounding tissue in Kelvin) was measured at all investigation points in comparison with the temperature difference at "intraop_pre" (mean values on all patients: ∆T intraop_pre = -2.64 K; ∆T intraop_post = -1.22 K, p < 0.0015; ∆T postop_1 = -0.54 K, p < 0.0001; ∆T postop_10 = -0.58 K, p < 0.0001). Intraoperative dynamic IR thermography showed typical pattern of non-pathological rewarming due to re-established flap perfusion after completion of the microvascular anastomoses. Static and dynamic IR thermography is a promising, objective method for intraoperative and postoperative monitoring of free-flap reconstructions in head and neck surgery and to detect perfusion failure, before macroscopic changes in the tissue surface are obvious. A lack of significant decrease of the temperature difference compared to surrounding tissue following completion of microvascular anastomoses and an atypical rewarming following a thermal challenge are suggestive of flap perfusion failure.

Strengths and limitations of microarray-based phenotype prediction: lessons learned from the IMPROVER Diagnostic Signature Challenge.

MOTIVATION: After more than a decade since microarrays were used to predict phenotype of biological samples, real-life applications for disease screening and identification of patients who would best benefit from treatment are still emerging. The interest of the scientific community in identifying best approaches to develop such prediction models was reaffirmed in a competition style international collaboration called IMPROVER Diagnostic Signature Challenge whose results we describe herein. RESULTS: Fifty-four teams used public data to develop prediction models in four disease areas including multiple sclerosis, lung cancer, psoriasis and chronic obstructive pulmonary disease, and made predictions on blinded new data that we generated. Teams were scored using three metrics that captured various aspects of the quality of predictions, and best performers were awarded. This article presents the challenge results and introduces to the community the approaches of the best overall three performers, as well as an R package that implements the approach of the best overall team. The analyses of model performance data submitted in the challenge as well as additional simulations that we have performed revealed that (i) the quality of predictions depends more on the disease endpoint than on the particular approaches used in the challenge; (ii) the most important modeling factor (e.g. data preprocessing, feature selection and classifier type) is problem dependent; and (iii) for optimal results datasets and methods have to be carefully matched. Biomedical factors such as the disease severity and confidence in diagnostic were found to be associated with the misclassification rates across the different teams. AVAILABILITY: The lung cancer dataset is available from Gene Expression Omnibus (accession, GSE43580). The maPredictDSC R package implementing the approach of the best overall team is available at www.bioconductor.org or http://bioinformaticsprb.med.wayne.edu/.

Design and evaluation of an AR-based thermal imaging system for planning reconstructive surgeries.

INTRODUCTION: Thermal imaging can be used for the non-invasive detection of blood vessels of the skin. However, mapping the results to the patient currently lacks user-friendliness. Augmented reality may provide a useful tool to superimpose thermal information on the patient. METHODS: A system to support planning in reconstructive surgery using a thermal camera was designed. The obtained information was superimposed on the physical object using a Microsoft HoloLens. An RGB, depth, and thermal camera were combined to capture a scene of different modalities and reconstruct a virtual scene in real time. To register the different cameras and the AR device, an active calibration target was developed and evaluated. A Vuforia marker was used to register the hologram in the virtual space. The accuracy of the projected hologram was evaluated in a laboratory setting with participants by measuring the error between the physical object and the hologram. RESULTS: The AR-based system was evaluated by 21 participants in a laboratory setting. The mean projection error is 10.3 ± 9.4 mm. The system is able to stream a three-dimensional scene with augmented thermal information in real time at 5 frames per second. The active calibration target can be used independently of the environment. CONCLUSION: The calibration target provides an easy-to-use method for the registration of cameras capturing the visible to long-infrared spectral range. The inside-out tracking of the HoloLens in combination with a Vuforia marker is not accurate enough for the intended clinical use.

NLRP3 promotes allergic responses to birch pollen extract in a model of intranasal sensitization.

Introduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest. As these PAMPs are recognized by specialized pattern recognition receptors (PRRs), this study aims at investigating the roles of intracellular PRRs and the inflammasome regulator NLRP3. Methods: We established a physiologically relevant intranasal and adjuvant-free sensitization procedure to study BP-induced systemic and local lung inflammation. Results: Strikingly, BP-sensitized Nlrp3-deficient mice showed significantly lower IgE levels, Th2-associated cytokines, cell infiltration into the lung, mucin production and epithelial thickening than their wild-type counterparts, which appears to be independent of inflammasome formation. Intriguingly, bone-marrow chimera revealed that expression of NLRP3 in the hematopoietic system is required to trigger an allergic response. Conclusion: Overall, this study identifies NLRP3 as an important driver of BP-induced allergic immune responses.

Immunofluorescence Visualization of Polycyclic Aromatic Hydrocarbon Mixtures in the Eastern Oyster Crassostrea virginica.

Bivalve mollusks including oysters have low metabolic potential and are therefore susceptible to accumulating high levels of lipophilic organic contaminants such as polycyclic aromatic hydrocarbons (PAHs). Human exposure to PAHs via consumption of this important commercial shellfish can be a serious public health concern in areas where high PAH contamination exists. Previous PAH immunohistochemical studies have been limited to laboratory-based exposures focusing on one or a few individual PAH compounds. To date, such studies have yet to explore PAH accumulation in oysters, known to have some of the highest levels of PAHs across different food products. Using a monoclonal antibody selective for a range of three- to five-ring PAHs, we present a method to detect and localize complex mixtures of PAHs in oyster tissues via fluorescent immunohistochemistry. Observed immunofluorescence intensity followed a similar trend as measured levels of PAHs in oyster interstitial fluid from PAH-contaminated sites and oysters exposed to the water accommodated fraction of crude oil. This method will be valuable in understanding internal partitioning mechanisms of PAH-exposed oysters and will have important applications in studies on PAH distribution in the tissues of additional organisms for environmental, medical, or veterinary purposes. Environ Toxicol Chem 2023;42:475-480. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Immune-mediated platelet depletion augments Alzheimer's disease neuropathological hallmarks in APP-PS1 mice.

In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.