Chair: Natalia Malek (Wroclaw University of Science and Technology, Wroclaw, Poland)

Symposium 11: Intersecting Pathways: Neuroinflammation in Neurodegenerative Disease

This symposium will explore the critical role of neuroinflammation in the progression of neurodegenerative diseases. It will feature studies assessing blood-brain barrier integrity and inflammation resolution mechanisms, highlighting the interplay between immune responses and cognitive decline, ultimately revealing novel therapeutic targets for managing neurodegenerative disorders.


Nico Melzer, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany

Role of B Cells and CD8+ T Cells in GABAA Receptor Autoimmune Encephalitis Pathogenesis

GABAA-R encephalitis, a rare autoimmune condition, involves antibodies targeting neuronal gamma-aminobutyric acid A receptors. We analyzed CD8+ and CD4+ T cell receptor repertoires in a patient with this condition using next-generation sequencing and single-cell techniques. A highly expanded B cell clone in the cerebrospinal fluid was identified, producing antibodies that bind to GABAA-R, verified by ELISA and immunohistochemistry. Patch-clamp studies showed these antibodies alter synaptic inhibition, increasing cortical neuron excitability. Additionally, a clonally expanded CD8+ T cell population was found in the cerebrospinal fluid and hippocampus, suggesting that neuron-targeting CD8+ T cells contribute independently to disease pathogenesis.

References:
1. Brändle SM, et al. Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABAA receptor encephalitis. Proc Natl Acad Sci U S A., 2021. doi: 10.1073/pnas.1916337118
2. Bracher A, et al. An expanded parenchymal CD8+ T cell clone in GABAA receptor encephalitis. Ann Clin Transl Neurol., 2020. doi: 10.1002/acn3.50974


Lidia Sabater, Hospital Clinic Barcelona, FCRB-IDIBAPS, Barcelona, Spain

Clinical perspective on Anti-IgLON5 Disease: Bridging Autoimmunity and Neurodegeneration in a Novel Neurological Disorder

Anti-IgLON5 disease is a newly recognized neurological condition that straddles the realms of autoimmunity and neurodegeneration. Patients typically experience a chronic and progressive course, characterized by gait instability, abnormal movements, bulbar dysfunction, and a unique sleep disorder involving obstructive sleep apnea and stridor. While the disease is defined by the presence of antibodies against IgLON5, a cell surface protein whose function is unclear, neuropathological investigations have identified an unusual tauopathy in the brainstem. The response to immunotherapy is generally poor, and delays in diagnosis, combined with the absence of progression biomarkers, hinder better outcomes. Understanding the disease’s pathogenesis is essential for addressing its complexities.

References:
1. Sabater L, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol., 2014. Erratum in: Lancet Neurol. 2015. doi: 10.1016/S1474-4422(14)70051-1
2. Gaig C, Sabater L. New knowledge on anti-IgLON5 disease. Curr Opin Neurol., 2024. doi: 10.1097/WCO.0000000000001271


Marta Kaminska, Jagiellonian University, Cracow, Poland

Assessing Blood-Brain Barrier Integrity and Neuroinflammation in Neurodegenerative Disease Using Mass Cytometry

The blood-brain barrier (BBB) serves as a critical interface between the brain tissue and peripheral blood, regulating the transport of metabolites and nutrients. Since vascular damage can be an early indicator of Alzheimer’s disease (AD), this study aimed to investigate the role of the periodontopathogen Porphyromonas gingivalis in BBB disruption and AD progression. Brain tissues from C57BL/6J and 5xFAD mouse models infected orally with P. gingivalis were analyzed using mass cytometry with a panel of 40 antibodies. Results showed increased neuroinflammation and reactive gliosis in the infected mice’s brain tissue, suggesting a link between P. gingivalis infection, BBB breakdown, and AD.

References:
1. Dominy SS,et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv., 2019. doi: 10.1126/sciadv.aau3333


Ewa Trojan, Maj Institute of Pharmacology, PAS, Cracow, Poland

Regulation of Inflammation Resolution in Age-Related Cognitive Decline and Neurodegenerative Pathology

Neurodegenerative disease progression is closely associated with neuroinflammation, in which microglia are vital players. While short-term inflammation is beneficial and its controlled resolution facilitates repair and homeostasis, disruptions in the resolution of inflammation (RoI) can lead to chronic inflammation. RoI is influenced by specialized pro-resolving mediators (SPMs), such as lipoxin A4 (LXA4), which activates the N-formyl peptide receptor-2 (FPR2). FPR2 is a versatile receptor that can trigger either pro-inflammatory or pro-resolving effects, depending on ligand structure. Our study examined age-related cognitive changes and RoI disturbances in wild-type and hAPPNL-F/NL-F KI male mice, revealing that aging impairs the availability of pro-resolving FPR2 ligands, leading to increased pro-inflammatory microglia polarization and FPR2 overactivation mediated by inflammatory ligands. These findings highlight FPR2 receptors as key regulators of the RoI process in age-related neurodegenerative pathology.

References:
1. Trojan E, et al. The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1-42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease. Mol Neurobiol., 2021. doi: 10.1007/s12035-021-02543-2
2. Trojan E, Frydrych J, Lasoń W, Basta-Kaim A. Prenatal stress increases the risk of the FPR2-related dysfunction in the brain’s resolution of inflammation: a study in the humanized APPNL−F/NL-F mouse model of Alzheimer’s disease. Curr Neuropharmacol., 2025. doi: 10.2174/011570159X345385241004060055

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