Immunometabolic Basis of Neurodegenerative Disorders

24.04.2026, Friday, 16:00-17:30

General focus of the symposium:

Several neurodegenerative disorders (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD) share the hallmark feature of pathological protein aggregation despite their distincy clinical manifestations. Across these disorders, misfolded or aggregated proteins disrupt fundamental homeostatic pathways and trigger glial activation, ultimately driving progressive neuronal loss.

Importantly, the impact of pathological protein aggregation in NDDs reflects cell- and context-specific vulnerabilities that are further shaped by systemic immunometabolic factors. Conditions, such as type 2 diabetes mellitus (DM2), obesity, and dyslipidemia are associated with increased risk and worse clinical course in AD and PD. In contrast, pre-clinical, as well as clinical studies in ALS consistently suggest protective effects of DM2, elevated body mass index (BMI), or dyslipidemia. These divergent observations underscore the overarching influence of systemic metabolic states and their differential effects on neurons and glia in determining NDD risk and progression.

The blood–brain barrier (BBB) sits at the intersection of this systemic-central dialogue. Systemic metabolic alterations reshape endothelial metabolism, transporter function, cytokine responsiveness, and barrier permeability, enabling peripheral inflammatory cues to access neural tissue more readily. These shifts can impact microglial activation, astrocytic reactivity, and neuronal health, positioning BBB as an active participant rather than a passive barrier for NDDs risk and progression.

This symposium brings these complementary perspectives to synthesize a unified immunometabolic framework for understanding NDDs. By examining how cellular metabolism, systemic metabolic states, and BBB function converge, the session will highlight shared mechanisms across NDDs. The session will further emphasise how insights from this integrated view can guide the development of therapeutic strategies aimed at boosting metabolic resilience, modulating neuroimmune interactions, or stabilising barrier integrity.

Chair: Ismail Gbadamosi (Wrocław)

16:00 Dr. Mootaz M. Salman

Univeristy of Oxford

"Targeting the Blood-Brain Barrier: New Frontiers in Neurodegeneration and Brain Health"

Neurodegenerative diseases are multifactorial and heterogeneous conditions and leading cause of morbidity and mortality. Our work aims to answer the question: how does inflammation-mediated blood-brain barrier (BBB) dysfunction lead to the development of neurodegeneration and whether we can stop it? Increasing evidence supports the involvement of BBB dysfunction in neurodegenerative disorders including Parkinson’s, Alzheimer's and small vessel dementia; it is evident that this dysfunction happens even before the onset of dementia. In-depth understanding of the cell-cell interactions and signalling pathways between the core elements of the BBB will help in defining and validating new therapeutic targets for the prevention of dementia. In our work, we developed advanced microfluidic 3D BBB-on-a-chip models using patient-derived iPSCs and human primary cells and identified a number of molecular targets that contribute to barrier integrity and function in astrocytes and pericytes. Our work provides new tools to understand lifelong brain health, describe the basis of BBB dysfunction in the occurrence and development of neurodegeneration, and provides a platform to develop new treatments for dementia and related CNS pathologies.

16:40 Ismail Gbadamosi

Translational Neuropsychiatry Research Group, Life Sciences and Biotechnology Center, Lukasiewicz Research Network–PORT Polish Center for Technology Development, Warsaw, Poland

"TDP-43-metabolism interplay in motor neurons: Implications for ALS pathophysiology"

TDP-43 nuclear depletion and cytoplasmic mislocalization are defining molecular features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Epidemiological evidence points to critical roles for metabolic cascades in ALS and PTLD pathogenesis, yet the role of TDP-43 in regulating brain energy metabolism remains unclear.

We aimed to examine the effects of TDP-43 dysfunction on motor neuronal and microglial metabolism and its functional consequences for neuronal health.

TDP-43 was depleted in mouse motor neuron- and microglia-like cells using RNA interference, followed by assessment of glycolytic flux, mitochondrial oxidative phosphorylation (OXPHOS), and cellular energy sensing.

TDP-43 loss induced divergent metabolic remodeling in a cell-type-specific manner. In motor neurons, TDP-43 depletion triggered a hypermetabolic state characterized by coordinated upregulation of glycolysis and mitochondrial OXPHOS, accompanied by impaired AMPK signalling, leading to sustained energetic demand. In contrast, microglia underwent a pronounced shift toward glycolysis without a corresponding increase in mitochondrial OXPHOS. This glycolytic reprogramming was functionally consequential, promoting exaggerated engulfment of healthy synaptoneurosomes. Importantly, bypassing glycolysis rescued the enhanced engulfment phenotype, supporting the notion that altered energy metabolism is a causal driver of pathological microglial behavior.

Collectively, these findings identify TDP-43 dysfunction as a driver of cell-type-specific metabolic rewiring, coupling neuronal hypermetabolism and impaired energy sensing with microglial glycolytic activation and maladaptive synaptic pruning. This neuron–microglia metabolic mismatch provides a mechanistic pathway by which TDP-43 pathology can cause both motor neuron stress and non-cell-autonomous synaptic injury, highlighting energy metabolism as a tractable therapeutic axis in ALS and FTD.

16:52 Natalia Stelmach

Wroclaw University of Science and Technology, Department of Chemical Biology and Bioimaging, Poland

"Rational Design of Subunit-Selective Immunoproteasome Inhibitors Relevant to Neuroinflammation"

Dysfunction of the proteasome and immunoproteasome (i20S) contributes to proteotoxic stress, chronic microglial activation and neuroinflammation in neurodegenerative disorders and chronic pain conditions. In previous work, we demonstrated that LPS-stimulated microglia and distinct brain regions of animals in the chronic constriction injury (CCI) model undergo strong i20S remodeling with upregulation of β1i, β2i, and β5i and changes in catalytic activity and gene expression. These findings underscore the need for subunit-selective chemical tools to dissect the immunoproteasome’s role in CNS pathology.

Here, we combined this biological framework with computational approach to design selective peptide-based inhibitors.

Using large libraries of natural and non-natural amino acids, we mapped positional preferences (P2–P6) across six catalytic β subunits (β1/β1i, β2/β2i, β5/β5i) and identified optimal residues that define subunit-specific recognition motifs. This enabled the rational construction of ideal peptides predicted to exhibit maximal selectivity.

Docking analyses using AutoDock Vina revealed distinct pocket geometries and interaction networks that explain subunit-selective binding and provide a structural basis for targeted inhibitor design.
Together, this framework links immunoproteasome biology with structure-guided design and offers new avenues for developing selective proteasome modulators relevant to neurodegeneration.

17:06 Alonso Cerdeño-Arévalo

Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Spain

"Comparative proteomic of the oculomotor region and the ventral spinal cord: identifying molecular signatures underlying neuronal resilience"

Amyotrophic Lateral Sclerosis (ALS) and Muscular Spinal Atrophy (MSA) lead to the degeneration of motor neurons. Despite their distinct aetiologies and clinical progression, neurons in the oculomotor (OCM) region display remarkable resilience compared to other motor neuron populations. Previous transcriptional studies suggest that differential motor neuron vulnerability may arise from cell‑type‑specific gene regulation and inherent molecular differences that modulate cellular responses to disease.

In this work, we investigate these differences at the protein level by comparing the “resilient” oculomotor (OCM) region with the “vulnerable” spinal cord (SC), aiming to identify potential neuroprotective molecular signatures.

Fresh frozen tissue from p63 ChAT-IRES-Cre::Ai9(RCL-tdT) mice (n=12, 6 males and 6 females) was processed for LC-MS/MS analysis. Raw LFQ data were annotated using MaxQuant, and downstream statistical analyses were performed using Perseus v1.6.15. Enrichment analyses were performed using both publicly available and licensed software tools, including Metascape, Ingenuity Pathway Analysis (IPA), and curated pipelines for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations using R.

Comparative proteomics analysis of the OCM and the SC revealed significant enrichment of pathways related to synapse organization, regulation, and signaling. In contrast, metabolic pathways associated with mitochondrial function and lipid metabolism were markedly downregulated in the OCM. Notably, molecules linked to motor neuron degeneration, such as SOD1 and SOD2, were upregulated in the OCM region.

The OCM region displays a unique protein signature linked to lipid and mitochondrial metabolism, and elevated antioxidant expression relative to the SC. These pathways may contribute to the intrinsic resilience of OCM neurons, in contrast to the vulnerability observed in spinal motor neuron populations affected in ALS and SMA.

17:19 Violeta Belickienė

Laboratory of Molecular Neurobiology, Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu Str. 4, Kaunas, Lithuania

"Circulating YRNAs as Novel Biomarkers in Parkinson's disease Diagnostics and Prognostics"

Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking disease modifying therapies, driving interest in extracellular vesicles (EVs) as carriers of regulatory proteins and non coding RNAs. Y RNAs form a substantial yet understudied component of EV cargo and may reflect disease related cellular states, but their cell type specificity, selective EV loading, and clinical relevance in PD remain poorly defined, especially for primate specific Y RNAs requiring human relevant systems.

This study aimed to characterize Y RNA expression in neural cells, determine their selective incorporation into EVs, and assess whether EV associated Y RNA profiles and ratios capture PD related biological and clinical features.

Y RNAs were extracted from four neural stem cell lines, four neural pathology–derived lines, their secreted EVs, and from patient serum derived EVs. RNA was converted to cDNA and quantified by RT qPCR. The study included PD patients, who underwent neurological, cognitive, and quality of life assessment, and healthy controls. Y RNA expression and ratios were evaluated across cell models and patient EVs to examine group differences, clinical associations, and diagnostic performance.

Y RNAs were differentially regulated across neural cell types, with pathological transformation disrupting their coordinated patterns. Y RNAs were also selectively packaged into EVs, with strong enrichment of RNY4 and relative exclusion of RNY1, indicating active sorting. In serum EVs, PD showed a distinct Y RNA profile: RNY3 related to disease presence, while RNY5 correlated with disease duration, severity, and functional decline. Inter Y RNA ratios provided more informative signals than absolute levels across cell models and patient samples.

Y RNAs emerge as selectively regulated EV cargo with diagnostic and prognostic relevance in PD.