Associations between <scp>TMEM106B</scp> C‐terminal fragment aggregation, age, and <scp>TDP</scp> ‐43 or tau pathology

Transmembrane protein 106B (TMEM106B) is a lysosomal glycoprotein whose genetic polymorphisms contribute to the severity of neurodegenerative disorders associated with TDP-43 pathology. Recent studies have revealed that TMEM106B can form amyloid filaments composed of C-terminal fragments (CTFs) in the human brain. In the present study, we explored the relationships between TMEM106B, age, TDP-43, and tau aggregates, and their roles in neurodegeneration. We used immunohistochemistry with an antibody against CTFs of TMEM106B on postmortem human brain fragments (amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia) from patients with and without TDP-43/tau pathology at different ages (6-94 years) and with different neurological conditions (subacute sclerosing panencephalitis, Alzheimer's disease, frontotemporal lobar degeneration, and neurologically healthy subjects). Our results revealed that TMEM106B CTF fibrillization is a common, nonspecific, diffuse, and age-dependent phenomenon (appearing after >52 years of age) that affects neurons and neuroglia (most numerous in astrocytes and oligodendrocytes) and broad neuroanatomical regions (most severe in the temporal cortex). We did not find TMEM106B CTF aggregates in young subjects with TDP-43/tau pathology (with subacute sclerosing panencephalitis), but we revealed differences in TMEM106B CTF fibrillization between Alzheimer's disease without TDP-43 pathology, frontotemporal lobar degeneration with TDP-43 pathology, and older healthy subjects without TDP-43/tau pathology. Our results suggest that TMEM106B CTF aggregation is an age-dependent phenomenon and may have a weak association with TDP-43 or tau pathology, shedding new light on the complex relationships among TMEM106B, TDP-43, and tau and the unclear role of TMEM106B fibril formation in the neurodegeneration process.