Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression

Anti-IgLON5 disease is a rare neurological disease at the intersection of autoimmunity and neurodegeneration. It is characterized by the presence of anti-IgLON5 antibodies and the development of a brainstem-dominant tau pathology. Recent research indicates that the tau pathology may develop in a time-dependent manner. A three-staged neuropathological classification of the disease has been recently suggested, ranging from no or minimal tau (stage 1) to the characteristic brainstem tau pathology (stage 3) as originally described. This study aimed to characterize the evolution of the disease-associated tauopathy more precisely and to further investigate the early neurodegenerative events in anti-IgLON5 disease. We analyzed the medullary region of 14 autopsy cases of anti-IgLON5 disease with different severity grades of tau pathology and varying disease durations, from 6 to 180 months, and compared our findings with five PSP cases and ten neurologically healthy controls by immunohistochemistry. We applied a broad panel of antibodies targeting different pathological tau post-translational modification sites and the nuclear membrane. In addition, we performed a cell culture of rat hippocampal neurons incubated with purified anti-IgLON5 antibodies to validate the results of the autopsy samples. Based on the tau burden in relation to the pathology stage and disease duration, we determined the chronological appearance of the different post-translational modifications of tau. Phosphorylation at Serine 422 was identified as one of the first alterations at stage 1 and showed an early neuronal nuclear staining with simultaneous anti-IgLON5 IgG4 deposits on the neuronal surface as observed by double immunolabeling. Nuclear membrane alterations were also evident by Lamin B1 staining. These were significantly more frequent at stage 1 as compared to controls and adopted the form of nuclear invaginations and crenellations. Crenellations of the nuclear membrane also developed in neuronal cell culture after three weeks of antibody incubation, supporting the autopsy findings in vitro. The development of cytoplasmic tau pathology occurs at later stages of the disease with a sequence of post-translational modifications, after an initial nuclear pathology. These new findings contribute to a better understanding of the early pathophysiological events in anti-IgLON5 disease and reinforce the concept of a secondary tauopathy related to an immune-mediated mechanism.