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

• Published in: Neurobiology of aging 2020-02, Vol.86, p.143-155
• Main Authors: Palese, Francesca, Bonomi, Elisa, Nuzzo, Tommaso, Benussi, Alberto, Mellone, Manuela, Zianni, Elisa, Cisani, Francesca, Casamassa, Alessia, Alberici, Antonella, Scheggia, Diego, Padovani, Alessandro, Marcello, Elena, Di Luca, Monica, Pittaluga, Anna, Usiello, Alessandro, Borroni, Barbara, Gardoni, Fabrizio
• Format: Article
• Language: English
• Subjects: AMPA receptors; Autoimmunity; Cerebrospinal fluid; Dementia; Glutamate; Synapses
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2019.10.015

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. •GluA3 autoantibodies affect glutamatergic neurotransmission in FTLD-tau patients.•GluA3 autoantibodies decrease glutamate release and GluA3 synaptic levels.•FTD patients show an increase of glutamate and D- and L-serine levels in the CSF.