Associations between TMEM106B C-terminal fragment aggregation, age, and TDP-43 or tau pathology

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Transmembrane protein 106B (TMEM106B) is linked to neurodegenerative disorders, particularly those involving TDP-43.
• Recent findings indicate TMEM106B C-terminal fragments (CTFs) can form amyloid filaments in the human brain.

Purpose of the Study:

• To investigate the relationships between TMEM106B, aging, TDP-43, and tau aggregates in neurodegeneration.
• To determine the prevalence and characteristics of TMEM106B CTF fibrillization across different age groups and neurological conditions.

Main Methods:

• Immunohistochemistry using an antibody against TMEM106B CTFs.
• Analysis of postmortem human brain tissue from individuals with and without TDP-43/tau pathology, aged 6–94 years.
• Examination of various brain regions including amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia.

Main Results:

• TMEM106B CTF fibrillization is a common, age-dependent phenomenon (observed >52 years), affecting neurons and neuroglia, particularly astrocytes and oligodendrocytes.
• Fibrillization was most severe in the temporal cortex and was not found in young subjects with TDP-43/tau pathology.
• Distinct patterns of TMEM106B CTF fibrillization were observed in Alzheimer's disease, frontotemporal lobar degeneration with TDP-43 pathology, and healthy older adults.

Conclusions:

• TMEM106B CTF aggregation is primarily an age-dependent process, not strongly associated with TDP-43 or tau pathology.
• The findings provide new insights into the complex interplay between TMEM106B, TDP-43, and tau in the context of aging and neurodegeneration.
• The precise role of TMEM106B fibril formation in the neurodegenerative process remains to be fully elucidated.