FTLD-TDP With and Without GRN Mutations Cause Different Patterns of CA1 Pathology

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Progranulin (PGRN) deficiency, caused by GRN gene mutations, is linked to frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A).
• PGRN is crucial for modulating microglial function in the central nervous system.
• Altered microglial function due to PGRN deficiency may contribute to FTLD-TDP pathogenesis.

Purpose of the Study:

• To investigate the relationship between GRN gene mutations, microglial function, and neuropathological features in the hippocampal CA1 region of FTLD-TDP type A patients.
• To compare FTLD-TDP type A cases with GRN mutations to sporadic cases regarding neuronal loss, TDP-43 inclusions, and microglial morphology.

Main Methods:

• Analysis of post-mortem brain tissue from FTLD-TDP type A patients with and without GRN mutations.
• Histopathological examination of the hippocampal CA1 region, focusing on neuronal counts, TDP-43 inclusions, and microglial morphology and PGRN expression.

Main Results:

• The CA1 sector showed less neuronal loss and more frequent TDP-43 inclusions in GRN mutation cases compared to sporadic cases.
• GRN mutation cases exhibited an increased presence of rod-like microglia with reduced PGRN expression in the CA1 region.
• These findings indicate a distinct neuropathological profile in the CA1 region associated with GRN mutation status.

Conclusions:

• GRN gene expression status influences TDP-43 inclusion profiles, neuronal numbers, and microgliosis in the CA1 sector of FTLD-TDP type A.
• Microglial PGRN deficiency and altered microglial morphology are implicated in the pathogenesis of FTLD-TDP type A.
• The study highlights the critical role of PGRN in maintaining neuronal health and regulating microglial responses in FTLD-TDP.