Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

Francesca Palese, Elisa Bonomi, Tommaso Nuzzo, Alberto Benussi, Manuela Mellone, Elisa Zianni, Francesca Cisani, Alessia Casamassa, Antonella Alberici, Diego Scheggia, Alessandro Padovani, Elena Marcello, Monica Di Luca, Anna Pittaluga, Alessandro Usiello, Barbara Borroni, Fabrizio Gardoni

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Abstract

Despite the great effort of the scientific community in the field, the pathogenesis of frontotemporal dementia (FTD) remains elusive. Recently, a role for autoimmunity and altered glutamatergic neurotransmission in triggering disease onset has been put forward. We reported the presence of autoantibodies recognizing the GluA3 subunit of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in about 25% of FTD cases. In this study, we evaluated the mechanisms involved in anti-GluA3 autoimmunity, through molecular/neurochemical analyses conducted on patients' brain specimens with frontotemporal lobar degeneration–tau neuropathology. We then corroborated these results in vivo in FTD patients with transcranial magnetic stimulation and glutamate, D-serine, and L-serine dosages in the cerebrospinal fluid and serum. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by transcranial magnetic stimulation, suggesting a significant impairment of indirect measures of glutamatergic neurotransmission in FTD patients compared with controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine, and L-serine levels in the cerebrospinal fluid.

Original languageEnglish
Pages (from-to)143-155
Number of pages13
JournalNeurobiology of Aging
Volume86
DOIs
Publication statusPublished - Feb 2020

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Keywords

  • AMPA receptors
  • Autoimmunity
  • Cerebrospinal fluid
  • Dementia
  • Glutamate
  • Synapses

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Palese, F., Bonomi, E., Nuzzo, T., Benussi, A., Mellone, M., Zianni, E., Cisani, F., Casamassa, A., Alberici, A., Scheggia, D., Padovani, A., Marcello, E., Di Luca, M., Pittaluga, A., Usiello, A., Borroni, B., & Gardoni, F. (2020). Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure. Neurobiology of Aging, 86, 143-155. https://doi.org/10.1016/j.neurobiolaging.2019.10.015