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

Abstract

A number of evidences has put forward new players in the pathogenesis of Frontotemporal Dementia (FTD) claiming for a role of autoimmunity and altered glutamate neurotransmission in triggering disease onset. We reported the presence of autoantibodies recognizing the GluA3 subunit of AMPA receptors in about 25% of FTD cases. Here we evaluated the mechanisms involved in anti-GluA3 autoimmunity in FTD, through molecular/neurochemical analyses conducted on patients' brain specimens, corroborated by Transcranial Magnetic Stimulation (TMS) and analysis of glutamate, D-serine and L-serine levels in the CSF. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing AMPA receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by TMS, suggesting a significant impairment of indirect measures of glutamate neurotransmission in FTD patients as compared to 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 CSF.

A multi-omics dataset for the analysis of Frontotemporal Dementia genetic subtypes

“…Moreover, neuronal loss can be primarily attributed to loss of excitatory neurons, while fractions of inhibitory are not significantly different to controls (Table S3). Our results therefore confirm findings from recent studies that found excitatory neurons to be especially vulnerable to tau pathology 19 and detected an important role of glutamatergic neurotransmission in FTD 20,21 . Closer examination of the KEGG pathway 'glutamatergic synapse' suggests that AMPA receptors are mainly affected, while we could not see signs of dysregulation for NMDA receptors (Fig.…”

Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

“…Together with the results of genome-wide association studies (GWAS), 210,211 new potential pathogenetic mechanisms have emerged, enhancing the arsenal of possible therapeutic strategies, including new insights from the role of autoimmunity. 191,[212][213][214] However, despite this progress, a precise definition of the specific pathogenetic path is still far from reach. Indeed, as depicted in this review, although the biological cascades leading to the specific protein (ie, Tau, TDP-43, FET)-driven neurodegeneration are still to be fully elucidated, they occur along common pathophysiological pathways.…”

“…174 Moreover, tDCS restored intracortical connectivity measures, evaluated with TMS, which have been shown to be impaired early in the disease course. [175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191] Interestingly researchers found that presymptomatic mutation carriers improved in cognitive tests after tDCS. 175 tDCS has been found to enhance theory of mind, the ability to understand and predict other people's behavior by attributing independent mental states to them, in patients with bvFTD.…”

Antibodies Against the NH2-Terminus of the GluA Subunits Affect the AMPA-Evoked Releasing Activity: The Role of Complement

“…The involvement of altered in-out movements of the ionotropic receptor relies on (i) the dynamic feature of the receptor under study and (ii) the results from biotinylation studies demonstrating that both the anti-GluA2 and anti-GluA3 antibodies elicited comparable modifications to the insertion of the GluA2 and the GluA3 subunits in synaptosomal plasma membranes. Notably, a recent study demonstrated in cortical specimens from patients suffering from frontotemporal lobar degeneration associated to an increase availability of anti-GluA3 auto-antibodies the onset of postsynaptic changes in the expression of scaffolding proteins (e.g., the GRIP1/PICK1 ratio) involved in AMPA receptor retention/internalization (27). The possibility that this adaptation might represent the consequence of impaired in-out movements of the GluA2 and 3 subunits due to the circulating anti-GluA autoantibodies and that it also could occur at the presynaptic level deserves attention and will be tackled in future studies.…”

“…We recently demonstrated that antisera of patients suffering from frontotemporal dementia enriched in anti-GluA3 antibodies impeded the releasing activity of presynaptic release-regulating AMPA autoreceptors in cortical synaptosomes (27). Based on these observations, we turned to commercially available anti-GluA antibodies to verify their impact on the functional activity of presynaptic release-regulating AMPA receptors in cortical glutamatergic nerve endings and possibly to predict the subunit composition of the receptor under study.…”