Laboratory Modeling of Synaptic Changes in Frontotemporal Dementia Patients' Brains
Innovative laboratory models using patient-derived neurons reveal synaptic loss and dysfunction in frontotemporal dementia, paving the way for new treatments.
Recent research from the University of Eastern Finland has demonstrated that neurons derived from skin biopsies of frontotemporal dementia (FTD) patients can effectively replicate the synaptic deterioration observed in the actual brains of these individuals. Using advanced stem cell technology, scientists generated induced pluripotent stem cell (iPSC) neurons from both patients carrying the C9orf72 gene repeat expansion and from those with sporadic forms of FTD, comparing them to neurons from healthy controls.
The cultured neurons included both excitatory and inhibitory types from various layers of the cerebral cortex, along with supporting astrocytes developed over extended culture periods. Notably, neurons from patients exhibited characteristic pathological features such as accumulations of RNA and dipeptide repeat (DPR) proteins associated with gene repeat expansion, alongside typical proteins like p62 and TDP-43 that are hallmarks in FTD brain tissue.
The study found a significant reduction in dendritic spine density—structures critical for synaptic connections—in neurons derived from both genetic and sporadic FTD patients, indicating synaptic loss at a cellular level. Moreover, when stimulated with neurotransmitters, these neurons showed impaired responses, suggesting disrupted neurotransmission processes.
Further analysis revealed alterations in gene expression related to synaptic integrity and neurotransmitter regulation, hinting at a compensatory response by neurons attempting to mitigate synaptic deficits. These findings imply that synapse loss and dysfunction are central to FTD pathology regardless of genetic background.
The research provides a powerful preclinical model for exploring disease mechanisms and testing therapeutic interventions. Future studies aim to uncover molecular details of synaptic deterioration, which could lead to the development of novel biomarkers and treatments for FTD. Additionally, this model offers a platform to evaluate the efficacy of drugs or electrical stimulation methods to restore synaptic function.
Overall, the study underscores the value of patient-derived neuronal models in understanding neurodegenerative diseases and opens pathways for targeted therapies aimed at preserving synaptic health.
Source: https://medicalxpress.com/news/2025-10-synaptic-brains-patients-frontotemporal-dementia.html
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