2. Academic Validation
  3. Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features

Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features

  • Brain Behav Immun. 2024 Mar 12:118:380-397. doi: 10.1016/j.bbi.2024.03.018.
Maria Italia 1,  Michela Salvadè 1,  Filippo La Greca 1,  Elisa Zianni 1,  Silvia Pelucchi 1,  Alessio Spinola 1,  Elena Ferrari 1,  Silvana Archetti 2,  Antonella Alberici 3,  Alberto Benussi 3,  Eino Solje 4,  Annakaisa Haapasalo 5,  Dorit Hoffmann 5,  Kasper Katisko 4,  Johanna Krüger 6,  Roberta Facchinetti 7,  Caterina Scuderi 7,  Alessandro Padovani 3,  Monica DiLuca 1,  Diego Scheggia 1,  Barbara Borroni 3,  Fabrizio Gardoni 8
Affiliations

Affiliations

  • 1 Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • 2 Department of Laboratories, Central Laboratory of Clinical Chemistry Analysis. ASST Spedali Civili, Brescia, Italy.
  • 3 Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • 4 Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Neuro Center, Neurology, Kuopio University Hospital, Kuopio, Finland.
  • 5 A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • 6 Research Unit of Clinical Medicine, Neurology, University of Oulu, Oulu, Finland; Neurocenter, Neurology, Oulu University Hospital, Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland.
  • 7 Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.
  • 8 Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy. Electronic address: [email protected].
PMID: 38485064 DOI: 10.1016/j.bbi.2024.03.018
Abstract

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Keywords

Animal model; Behaviour; Personalized medicine; Positive allosteric modulators; Tau.

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