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Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10 + 16 mutation
Owen Dando1,2, Robert McGeachan1,2, Jamie McQueen1,2
1UK Dementia Research Institute, The University of Edinburgh, Edinburgh, UK.
Neuropathology and Applied Neurobiology
|August 21, 2024
Summary
This study reveals that a specific MAPT gene mutation (10+16) leads to synaptic dysfunction and neuroinflammation in frontotemporal dementia (FTD). These findings highlight synaptic pathology as a key factor in FTD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Mutations in the MAPT gene cause tauopathies, including frontotemporal dementia (FTD).
- Synapse loss is a key feature of Alzheimer's disease and other tauopathies.
- Molecular mechanisms of synapse degeneration in primary tauopathies are not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms of synapse degeneration in FTD caused by the MAPT intronic exon 10+16 mutation.
- To examine post-mortem brain tissue from individuals with FTD (FTDtau10+16) and controls.
Main Methods:
- RNA sequencing and histopathology were used on temporal and visual cortex tissues.
- Comparison was made between 12 FTDtau10+16 cases and 13 age, sex, and RNA integrity matched controls.
Main Results:
- RNA sequencing showed significant downregulation of genes related to synaptic function.
- Biological pathways involved in transcriptional regulation, DNA damage response, and neuroinflammation were upregulated.
- Histopathology confirmed increased pathological tau, loss of presynaptic proteins, and increased phospho-tau colocalization with synapses.
Conclusions:
- Synaptic pathology is implicated in the pathogenesis of FTDtau10+16.
- The MAPT 10+16 mutation contributes to neurodegeneration through synaptic dysfunction and inflammation.
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