Ludwig Aigner

CD8⁺ T cells infiltrate the brain parenchyma of patients with Alzheimer’s disease (AD), where they localize near microglia and neurons. Although recent studies have revealed that they can clonally expand and possess a unique phenotype, their contribution to disease pathogenesis remains poorly understood. To investigate the role of these cells in AD, we first performed exploratory immunopeptidome profiling in aged transgenic AD (APP/PS1) mice to identify potential major histocompatibility complex class I-presented antigens that might drive CD8⁺ T cell recruitment. Surprisingly, no peptides were found to be overrepresented in transgenic compared with control brains, suggesting the absence of a dominant antigenic signature. We next characterized brain-infiltrating CD8⁺ T cells by flow cytometry and found that, in aged APP/PS1 mice, these cells exhibit a tissue-resident phenotype distinct from their circulating counterparts. To assess their functional relevance, we induced short-term CD8⁺ T cell depletion in two-year-old APP/PS1 mice using anti-CD8 antibody injections over three days and subsequently analyzed brain pathology and gene expression. CD8⁺ T cell depletion effectively reduced CD8⁺ T cell numbers in both blood and brain. Although amyloid plaque burden remained unchanged, female mice showed reduced LAMP1 ⁺ dystrophic neurites surrounding plaques and decreased phosphorylated tau deposition. These effects were accompanied by a modest increase in microglial abundance and elevated hippocampal Il1b expression. Collectively, these findings indicate that brain-resident CD8⁺ T cells contribute to specific aspects of AD-related neurodegeneration in a potential sex-dependent manner (although further experiments are needed), supporting a previously underappreciated role for CD8⁺ T cells in AD progression.

Purpose: Neurogenic lower urinary tract dysfunction (nLUTD) develops in nearly all patients after spinal cord injury (SCI). Evolving neuroinflammation is considered a key driver of secondary injury and is associated with worsening outcomes. However, few studies have examined treatments for nLUTD after SCI that specifically target these processes. This study investigated whether early montelukast therapy targeting proinflammatory leukotrienes improves long-term urological function and reduces pathological bladder remodeling.Methods: Female Lewis rats received a permanently implanted urinary catheter and underwent contusion SCI (Th8/Th9) or sham surgery. Daily montelukast treatment began 1 day after injury and continued throughout the 2- or 6-month follow-up period. Injury severity and regeneration were evaluated using the Basso-Beattie-Bresnahan locomotor score and microcomputed tomography of the spinal cord. Bladder function was assessed through weekly urodynamic recordings in awake animals, and bladder structure was assessed by histological measurement of wall thickness. Transcriptomic and proteomic analyses were used to characterize the molecular processes underlying bladder remodeling.Results: Spinal cord tissue damage and functional impairment were comparable across animals, regardless of treatment. Montelukast did not improve urodynamic outcomes and was associated with transiently poorer functional scores during early recovery. Bladder wall thickness increased after SCI and was greatest in the treated groups, suggesting ongoing remodeling. Transcriptomic and proteomic analyses demonstrated marked activation of immune and contractility-related pathways in treated animals at 2 months. Animals followed for the longer period showed intensified immune signaling, indicating sustained inflammatory activity.Conclusions: Early montelukast treatment did not improve functional or structural urological outcomes after contusion SCI. The unfavorable functional trends and intensified inflammatory and injury-related pathways suggested adverse effects rather than therapeutic benefit under the conditions studied. These findings may indicate the importance of injury model-specific mechanisms and of dose and timing when developing anti-inflammatory strategies for SCI-induced nLUTD.

Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive synaptic and neuronal loss, amyloid-β deposition, hyperphosphorylated tau accumulation, and chronic neuroinflammation, traditionally attributed primarily to the innate immune system. Increasing evidence, however, implicates the adaptive immune system as an active contributor to AD pathogenesis and progression. This emerging perspective has stimulated the development of immunomodulatory strategies aimed at mitigating cognitive decline and neuropathological hallmarks of the disease. In this review, we examine how adaptive immune responses change throughout the course of AD, integrating findings from both human studies and animal models while emphasizing the temporal dynamics of these alterations. We critically evaluate areas of consensus and controversy in the field, highlighting how differences in experimental models, disease stages, and methodological approaches contribute to divergent findings. Finally, we assess current therapeutic strategies targeting adaptive immunity, discussing their potential mechanisms of action and identifying key therapeutic windows and routes of administration that may maximize efficacy. By providing a comprehensive overview of adaptive immune involvement in AD, this review aims to inform the development of more precise and effective immunomodulatory interventions.

Lipoprotein apheresis is a highly effective and well-established extracorporeal therapy designed to remove lipoproteins from human circulation on a large scale, particularly in patients with progressive cardiovascular diseases when conventional treatments fail to achieve adequate lipoprotein reduction. Beyond its lipid-lowering capabilities, therapeutic apheresis is used to eliminate pathogenic substances, such as autoantibodies and immune complexes, and to exert immunomodulatory effects. Recent research highlights its potential to reduce inflammatory mediators, making it a promising intervention for conditions associated with systemic inflammation, including neurodegenerative diseases and post-infectious syndromes. In addition to its established applications, therapeutic apheresis is being explored as a novel approach to address emerging environmental health challenges, such as the accumulation of per- and polyfluoroalkyl substances (PFAS) and micro- and nanoplastics (MNPs) in living organisms. These pollutants, which are increasingly pervasive in the environment, pose significant health risks, including metabolic disruption, carcinogenesis, and neuroinflammation. Recognizing the urgency of this issue, institutions such as the US Department of Health and Human Services have initiated research programs to develop methods to monitor and remove these contaminants from the human body. Here, our preliminary findings suggest that therapeutic apheresis may represent a promising approach for reducing environmental toxins, alongside its established role in lowering lipoproteins and inflammatory biomarkers, and warrants further systematic clinical investigation. This is based on the hypothesis that PFAS and MNPs form aggregates with lipids and proteins, suggesting that therapeutic apheresis could be an ideal method for clearance. In the initial results, we observed decreases in both PFAS and MNP levels in patient blood and sequestered plasma following double filtration plasmapheresis, although responses varied across individuals and analytes. Tissue and in vitro studies using imaging and functional bioassays may be suitable for demonstrating the potential of apheresis to remove PFAS and MNPs, as well as for assessing the impact of MNPs on cell viability, inflammation, and secretome profiles. These findings could serve as clinical surrogates to guide treatment frequency and evaluate the sustainability of therapeutic apheresis in mitigating health risks associated with environmental pollutants. While larger, well-designed clinical trials are needed to confirm these benefits, these early results could lay the groundwork for future research and clinical applications.

Alzheimer’s disease (AD) progression has been associated with the presence of brain-resident CD8 ⁺ T cells, and recent studies suggest a potential role of the CXCL16-CXCR6 axis in their recruitment to the brain. Here, we examined publicly available single-cell RNA sequencing datasets revealing that in the mouse brain, the receptor Cxcr6 is mainly expressed by CD8 ⁺ T cells, while the expression of its ligand Cxcl16 is predominantly observed in microglial cells. We found higher levels of Cxcl16 and Cxcr6 expression in APP/PS1 compared to wild-type mice. Furthermore, in vitro experiments using immortalized and primary murine cells suggested that Cxcl16 expression is driven by Aβ pathology. In contrast to our expectations, no changes in the number of Cxcr6 ⁺ CD8 ⁺ cells was evident in the brains of microglia-depleted APP/PS1 mice, treated with the CSF1R antagonist PLX5622. This was related to an increased compensatory Cxcl16 expression by depletion-resistant microglia or by other brain-resident myeloid cells. Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6 ⁺ CD8 ⁺ T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8 ⁺ T cell recruitment to the brain.

Spinal cord injury (SCI) frequently leads to neurogenic lower urinary tract dysfunction, for which appropriate bladder management is essential. While clinical care relies on continuous low-pressure drainage in the acute phase, rat models commonly use twice-daily manual bladder expression—a method known to generate high intravesical pressures and retention. This study evaluated the impact of this standard practice on bladder tissue remodeling by comparing it to continuous drainage via high vesicostomy in a rat SCI model. 32 female Lewis rats underwent thoracic contusion SCI and were assigned to either manual expression or vesicostomy-based bladder management. Over eight weeks, locomotor recovery, wound healing, and bladder histology were assessed. Vesicostomy proved technically simple but required tailored wound care and calibration. Results showed significantly greater bladder wall thickness, detrusor muscle hypertrophy, urothelial thickening, collagen deposition, and mast cell infiltration in the manual expression group compared to both vesicostomy and controls. In contrast, vesicostomy animals exhibited near-control levels across most parameters. These findings highlight that commonly used bladder emptying protocols in rat SCI models may overestimate structural bladder changes and inflammatory responses. Refined drainage strategies such as vesicostomy can minimize secondary damage and improve the translational relevance of preclinical SCI research.

JOURNAL/nrgr/04.03/01300535-202606000-00057/figure1/v/2026-04-16T195327Z/r/image-tiff In Alzheimer’s disease, microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of Alzheimer’s disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis, and microglial responses. We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer’s disease pathology. The objective of this study is to investigate the effects of Alzheimer’s disease serum on microglial phagocytosis. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer’s disease ( n = 30) and age-matched controls ( n = 30) (PRODEM study) on microglial phagocytosis. Exposure to Alzheimer’s disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB ( TFEB ) and of ATPase H ⁺ transporting lysosomal V1 subunit B2 ( ATP6V1B2 ), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to the serum of future Alzheimer’s disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls, depending on the presence of the apolipoprotein E ε4 allele in the Alzheimer’s disease patients. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid. We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with Alzheimer’s disease blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2 , possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels, suggesting an important role for dietary eicosapentaenoic acid in microglial function.

Bladder dysfunction is among the most drastic and quality-of-life-reducing conditions after spinal cord injury (SCI). Neuroinflammation in the lower urinary tract (LUT) after SCI could be a key driver of neurogenic bladder dysfunction and tissue fibrosis. Leukotrienes, a group of highly active lipid mediators, are potent inflammatory mediators. Here, we explored the potential of early montelukast (MLK) therapy, a cysteinyl leukotriene receptor 1 antagonist, on LUT function and structure four weeks after severe SCI in rats. Rats (strain Lewis, female, n = 50) received a permanent bladder catheter, followed by a complete T9 spinal cord transection. MLK was given daily, starting on day one post-injury. Bladder and locomotor function were regularly assessed. Bladder tissue was histologically and immunhistochemically analyzed. Post-SCI, MLK concentrations in plasma and cerebrospinal fluid were clinically relevant. MLK improved bladder functionality. MLK had no impact on smooth muscle alignment and uroepithelial integrity at this early SCI time point. This pilot study gave first insights into early, continuous oral MLK treatment with the first promising results of preserved LUT function and possible subsequent improved tissue integrity.