PATHOLOGICAL IMPLICATIONS OF ANTI-GLUA3 ANTIBODIES IN FRONTOTEMPORAL DEMENTIA: FROM ANIMAL MODEL TO RESCUE STRATEGY

Over the last two decades, growing attention has been paid to the role of autoantibodies that target brain antigens in disorders of the central nervous system. Within this field, several studies detected anti-GluA3 antibodies in the serum of patients with autoimmune encephalitis and epilepsy. More recently, our research group identified anti-GluA3 antibodies in 20%–25% of patients with frontotemporal dementia (FTD), introducing novel implications for a pathogenic role of glutamate receptor autoantibodies in neurodegenerative diseases. Although previous in vitro studies showed that anti-GluA3 autoantibodies affect glutamatergic neurotransmission through different mechanisms, the impact of these autoantibodies on cognitive and social functions in vivo is still unknown, as well as the biological substrates of these putative modifications. To address this gap of knowledge and better dissect the contribution of anti-GluA3 autoantibodies to the above-mentioned neurological conditions, in the present study, we employed two models of in vivo administration of anti-GluA3 antibodies isolated from patients (anti-GluA3 hIgGs) to mice. First, we demonstrated that a single injection of anti-GluA3 hIgGs into the lateral ventricles induced profound molecular and morphological alterations into the prefrontal cortex of mice. Accordingly, mice presented significant changes in recognition memory and impairments in social behavior and in social cognitive functions. Given the negative effects of acute GluA3 hIgGs administration on synapses, behavior, and cognition, whether and how the chronic presence of autoantibodies triggers a neurodegenerative process and the association between this process and the appearance of FTD-related neuropathological and behavioral signature should be further investigated. Thus, we developed a chronic model by infusing mice with anti-GluA3 hIgGs for one month through an intracerebroventricular cannula. Data showed that chronic anti-GluA3 hIgGs administration in mice mediated the internalization of GluA3-containing AMPARs and led to selective accumulation of the phosphorylated form of tau in the post-synaptic fraction and dendritic spine loss in the prefrontal cortex of mice. Remarkably, we detected an increase in p-tau levels in cerebrospinal fluid of FTD patients positive for anti-GluA3 hIgGs (anti-GluA3-Ab+) compared with negative ones. In addition, mice chronically treated with anti-GluA3 hIgGs exhibited behavioral disturbances that mostly reflected the deficits detected in anti-GluA3-Ab+ patients, such as apathy, binge-like eating, and impulsivity. Finally, anti-GluA3 hIgG-mediated alterations were rescued in the chronic animal model by enhancing glutamatergic neurotransmission by a positive allosteric modulator of AMPAR. Overall, our study clarified the contribution of anti-GluA3 antibodies to central nervous system symptoms and pathology and identified a new subgroup of FTD patients. Our findings will be instrumental in the development of a therapeutic personalized medicine strategy for anti-GluA3-Ab+ patients.