Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target

Abstract

Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.

Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients

“…First, an increased prevalence of autoimmune diseases has been reported in FTLD patients compared to controls [45][46][47] and second, FTLD seems to be inversely linked to cancer [48], which may suggest alterations in the immune system or responses. Interestingly, the contribution of autoimmune mechanisms and genetic variation in loci associated with the immune system in FTLD were also suggested in recent studies [15,[49][50][51]. In line with these patient-derived data, C9orf72 repeat expansion has been linked to disturbances in the immune system [52], e.g., in mouse models with loss of function of the C9orf72 gene, which indicate a severe autoimmune phenotype, high mortality rate, and increased levels of proinflammatory cytokines and signs of neuroinflammation [16,17,52,53].…”

The Association Between Frontotemporal Lobar Degeneration and Bullous Pemphigoid

“…al (2014) linked FTLD patients with the HLA locus 6p21.3, suggesting possibly altered immune system functions in FTLD. Also, increased concentrations of anti-AMPA GluA3 antibodies were detected in patients with FTLD [11]. Recently, we discovered that prevalence of cancer is significantly lower in FTLD patients compared to neurologically healthy controls and AD patients [38], and that the C9orf72 repeat expansion may affect the prevalence of immunological diseases in FTLD [27].…”

“…However, the exact mechanisms underpinning FTLD pathogenesis remain thus far unclear. Recent studies have associated FTLD with possible dysfunctions in the immune system [8][9][10][11]. For example, C9orf72 knock-out murine models show increased levels of cytokines and autoantibodies and develop fatal autoimmune disease phenotypes [8,9].…”

Neuronal surface autoantibodies in dementia: a systematic review and meta-analysis

“…Eight studies met the inclusion criteria [9,19,[28][29][30][31][32][33]. However, one study [9] was subsequently excluded due to having an overlapping sample with a larger study [30].…”

“…However, one study [9] was subsequently excluded due to having an overlapping sample with a larger study [30]. A second study examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies only [28] and so was excluded from the meta-analyses. Six remaining studies examined NMDAR antibodies and were included in the meta-analysis [19,[29][30][31][32][33].…”