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Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.
Italia, Maria; Salvadè, Michela; La Greca, Filippo; Zianni, Elisa; Pelucchi, Silvia; Spinola, Alessio; Ferrari, Elena; Archetti, Silvana; Alberici, Antonella; Benussi, Alberto; Solje, Eino; Haapasalo, Annakaisa; Hoffmann, Dorit; Katisko, Kasper; Krüger, Johanna; Facchinetti, Roberta; Scuderi, Caterina; Padovani, Alessandro; DiLuca, Monica; Scheggia, Diego; Borroni, Barbara; Gardoni, Fabrizio.
Afiliación
  • Italia M; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Salvadè M; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • La Greca F; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Zianni E; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Pelucchi S; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Spinola A; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Ferrari E; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Archetti S; Department of Laboratories, Central Laboratory of Clinical Chemistry Analysis. ASST Spedali Civili, Brescia, Italy.
  • Alberici A; Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • Benussi A; Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • Solje E; Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Neuro Center, Neurology, Kuopio University Hospital, Kuopio, Finland.
  • Haapasalo A; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Hoffmann D; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Katisko K; Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Neuro Center, Neurology, Kuopio University Hospital, Kuopio, Finland.
  • Krüger J; 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.
  • Facchinetti R; Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.
  • Scuderi C; Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.
  • Padovani A; Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • DiLuca M; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Scheggia D; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy.
  • Borroni B; Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • Gardoni F; Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy. Electronic address: fabrizio.gardoni@unimi.it.
Brain Behav Immun ; 118: 380-397, 2024 May.
Article en En | MEDLINE | ID: mdl-38485064
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoanticuerpos / Degeneración Lobar Frontotemporal Límite: Animals / Humans Idioma: En Revista: Brain Behav Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / CEREBRO / PSICOFISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoanticuerpos / Degeneración Lobar Frontotemporal Límite: Animals / Humans Idioma: En Revista: Brain Behav Immun Asunto de la revista: ALERGIA E IMUNOLOGIA / CEREBRO / PSICOFISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Países Bajos