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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 at The University of Edinburgh, Edinburgh, United Kingdom.
Medrxiv : the Preprint Server for Health Sciences
|April 22, 2024
Summary
Frontotemporal dementia with tau pathology (FTDtau) involves synapse loss. This study found that a specific MAPT mutation leads to reduced synaptic gene expression and increased neuroinflammation, contributing to FTDtau pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Mutations in the MAPT gene cause autosomal dominant tauopathies, such as frontotemporal dementia (FTD).
- Synapse loss is a key feature of tauopathies and correlates with cognitive decline.
- Molecular mechanisms driving synapse degeneration in primary tauopathies are not well understood.
Approach:
- Examined post-mortem brain tissue from individuals with FTD caused by the MAPT intronic exon 10+16 mutation.
- Utilized RNA sequencing and histopathology on temporal and visual cortex.
- Compared FTDtau cases with age, sex, and RNA integrity matched controls.
Key Points:
- Substantial downregulation of synaptic function-associated gene expression was observed in FTDtau brains.
- Upregulated pathways included transcriptional regulation, DNA damage response, and neuroinflammation.
- Histopathology revealed increased pathological tau, loss of presynaptic proteins, and tau-synapse colocalization.
Conclusions:
- The MAPT exon 10+16 mutation leads to synaptic pathology in FTDtau.
- Synaptic degeneration is a likely contributor to the pathogenesis of this FTD subtype.
- Findings highlight the role of tau pathology in synapse loss in primary tauopathies.
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