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

Symposium 12: 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
A disclosure of any potential conflicts of interest: None


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
A disclosure of any potential conflicts of interest: None


Natalia Malek, Wroclaw University of Science and Technology, Wroclaw, Poland

Application of Activity-Based Probes for Visualizing Alterations in Proteasome and Immunoproteasome Function in Neuroinflammation

Proteostasis is essential for the regulation of protein synthesis, folding, and degradation within cells. When this balance is disrupted, it can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s, which are marked by protein inclusions. Dysregulation often stems from altered catalytic activity of the 20S proteasome and immunoproteasome subunits. This study aimed to investigate how inflammation affects the activity of these subunits in human microglial cell lines. Our methods included transcriptomic analysis via RT-qPCR, proteomic analysis using Western blotting, and activity profiling with activity-based probes (ABPs). Results indicated increased expression of β1 and β5 subunits, along with altered activity levels, highlighting potential therapeutic targets for neurodegenerative conditions.

References:
1. Malek N, Gladysz R, Stelmach N, Drag M. Targeting Microglial Immunoproteasome: A Novel Approach in Neuroinflammatory-Related
Disorders. ACS Chem Neurosci. 2024 Jul 17;15(14):2532-2544. doi: 10.1021/acschemneuro.4c00099. Epub 2024 Jul 6. PMID: 38970802; PMCID:
PMC11258690.
2. Gladysz R, Malek N, Rut W, Drag M. Investigation of the P1′ and P2′ sites of IQF substrates and their selectivity toward 20S proteasome subunits. Biol Chem. 2022 Nov 16;404(2-3):221-227. doi: 10.1515/hsz-2022-0261. PMID: 36376064.
A disclosure of any potential conflicts of interest: None


Jakub Frydrych, 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
A disclosure of any potential conflicts of interest: None

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