TY - JOUR
T1 - Anti-GluA3 antibodies in frontotemporal dementia
T2 - effects on glutamatergic neurotransmission and synaptic failure
AU - Palese, Francesca
AU - Bonomi, Elisa
AU - Nuzzo, Tommaso
AU - Benussi, Alberto
AU - Mellone, Manuela
AU - Zianni, Elisa
AU - Cisani, Francesca
AU - Casamassa, Alessia
AU - Alberici, Antonella
AU - Scheggia, Diego
AU - Padovani, Alessandro
AU - Marcello, Elena
AU - Di Luca, Monica
AU - Pittaluga, Anna
AU - Usiello, Alessandro
AU - Borroni, Barbara
AU - Gardoni, Fabrizio
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - AMPA receptors
KW - Autoimmunity
KW - Cerebrospinal fluid
KW - Dementia
KW - Glutamate
KW - Synapses
UR - http://www.scopus.com/inward/record.url?scp=85076231173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076231173&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2019.10.015
DO - 10.1016/j.neurobiolaging.2019.10.015
M3 - Article
C2 - 31784278
AN - SCOPUS:85076231173
VL - 86
SP - 143
EP - 155
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -