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Project Topic
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Tauopathies are neurodegenerative diseases, defined by loss of neurons and depositions of misfolded tau. A few years ago, anti-IgLON5 disease has been discovered, a neurological syndrome and subtype of autoimmune encephalitis defined by the presence of IgLON5 antibodies. It frequently resembles a neurodegenerative disease as it can present with dementia and is defined by histopathological tau depositions. Recent evidence supports a primary pathogenic role for the IgLON5 antibodies, while the tau hyperphosphorylation, aggregation and neurodegeneration seem to come as a consequence (inflammation first, neurodegeneration second). Our own work also suggest that early immunotherapy can prevent occurrence or deterioration of neurodegeneration. However, the mechanisms by which this adaptive neuronal autoimmunity leads to neurodegeneration remain unresolved.
IGNITEMIND addresses the link between adaptive neuroinflammation and tau hyperphosphorylation from an innovative and novel angle, using anti-IgLON5 disease as a model. Our hypothesis is that neuroinflammation by IgLON5 antibodies can cause tau hyperphosphorylation, aggregation and subsequent neurodegeneration. We aim at measuring multi-parameter biomarkers of neuroinflammation to enhance the understanding of underlying contributions of adaptive immunity. The role of neuroinflammation will be a target for future therapies, potentially expanding to more frequent tauopathies.
Within IGNITEMIND, we will combine the clinical expertise and biobanks of several renowned institutes in both autoimmune encephalitis and dementia with cutting edge research techniques. We will compare anti-IgLON5 disease and controls investigating several diseases stages (early and later disease and post-mortem). We will combine deep clinical phenotyping with 1) single cell RNA sequencing in paired fresh CSF and peripheral blood samples from treatment-naïve patients; 2) clone recombinant human monoclonal IgLON5 IgG, derived from BCR in the CSF scRNAseq data; 3) single cell proteomics (CyTOF) in PBMC, to compare to scRNAseq data; 4) proximity extension assay Olink® Explore proteomics in treatment-naive and later stage CSF; 5) immunohistochemistry on brain tissue for tau depositions, tau ratios and expression of IgLON family proteins as well as mass-spectrometry-based phosphoproteomics [from well-preserved snap-frozen brain tissue from anti-IgLON5 patients]; 6) single nucleus RNA sequencing of frontal cortex, temporal cortex, hippocampus and hypothalamus from IgLON5 brain tissue; 7) laser capture microdissection from frozen brain tissue to detect clonally expanded T and B cells; 8) neurodegenerative marker profiling in paired CSF and serum; 9) adding purified IgLON5 IgG and monoclonal, recombinant, patient-derived human IgG to cultures of patients’ human-iPSC derived neurons to assess the hyperphosphorylation and aggregation of tau, neuron cytoskeletal properties and viability; and 10) employing activity-based probes (ABPs) to investigate the contribution of cathepsins B, L, and S in the formation of tau deposits and the underlying pathomechanisms of anti-IgLON5 disease.
Together, our consortium is uniquely suited to the task of multi-omics, disease-spanning analysis of anti-IgLON5 disease. We combine high-profile experts in clinical neurology, neuroinflammation, neuropathology and neurodegeneration, world-leaders in the field of autoimmunity and neurodegeneration in a transnational, well-established network.
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