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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532270 | PMC |
| http://dx.doi.org/10.1038/s41598-017-06117-y | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.
Brain Behav Immun
May 2024
Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, Milan, Italy. Electronic address:
Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet.
View Article and Find Full Text PDFGluA3 autoantibodies induce alterations in dendritic spine and behavior in mice.
Brain Behav Immun
October 2021
Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, 20133 Milan, Italy. Electronic address:
Article Synopsis
- Autoantibodies targeting the GluA3 subunit of AMPA receptors are linked to various neurological conditions, including Rasmussen's encephalitis and frontotemporal dementia (FTD), indicating their potential role in cognitive deficits.
- Using a mouse model, researchers found that injecting anti-GluA3 immunoglobulin G (IgG) led to reduced levels of GluA3-containing AMPA receptors in the prefrontal cortex and significant changes in memory and social behavior.
- The effects of the anti-GluA3 IgG were temporary, with noticeable behavioral and molecular alterations being absent 10-14 days after injection, suggesting a transient impact on synaptic function related to FTD.
Antibodies Against the NH-Terminus of the GluA Subunits Affect the AMPA-Evoked Releasing Activity: The Role of Complement.
Front Immunol
July 2021
Pharmacology and Toxicology Section, Department of Pharmacy, DIFAR, Genoa, Italy.
Article Synopsis
- Antibodies targeting the amino-terminal domain of receptor subunits influence transmitter release efficiency in isolated nerve endings, supporting their presence and suggesting their composition.
- Western blot and confocal microscopy identified the presence of GluA1 to GluA4 receptor subunits in cortical synaptosomes, confirming the existence of AMPA autoreceptors that regulate presynaptic release.
- Modified synaptosomes, treated with specific antibodies, showed increased densities of GluA2 and GluA3 and enhanced AMPA-induced glutamate release, indicating a potential role for these antibodies in altering synaptic activity.
Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure.
Neurobiol Aging
February 2020
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. Electronic address:
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.
View Article and Find Full Text PDFToward a Glutamate Hypothesis of Frontotemporal Dementia.
Front Neurosci
March 2019
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Frontotemporal dementia (FTD) is a heterogenous neurodegenerative disorder, characterized by diverse clinical presentations, neuropathological characteristics and underlying genetic causes. Emerging evidence has shown that FTD is characterized by a series of changes in several neurotransmitter systems, including serotonin, dopamine, GABA and, above all, glutamate. Indeed, several studies have now provided preclinical and clinical evidence that glutamate is key in the pathogenesis of FTD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!