Transmembrane protein 106B amyloid is a potential off-target molecule of tau PET tracers in the choroid plexus

Tau positron emission tomography (PET) has become an essential tool for the clinical diagnosis of neurodegenerative diseases and the study of tau pathology in the brain. However, some tau tracers exhibit off-target binding in the basal ganglia, choroid plexus, and meninges. Recently, transmembrane protein 106B (TMEM106B) was identified to form novel amyloid filaments in the brain during aging. In this study, we explored the possibility that TMEM106B aggregates might be responsible for off-target binding of tau PET tracers in the choroid plexus.

The binding properties of ¹⁸F-labeled tau and amyloid tracers against choroid plexus tissues from postmortem human brains were evaluated through in vitro autoradiography and in vitro binding assays and compared with histochemical staining.

Autoradiography showed strong binding of [¹⁸F]PM-PBB3 followed by [¹⁸F]flortaucipir in the choroid plexus. Immunostaining of the same sections revealed a high level of transmembrane protein 106B aggregates, which are thioflavin-S-labeled Biondi ring structures, in the choroid plexus epithelium and co-localization with PM-PBB3-stained structures. In contrast, co-localization of flortaucipir with TMEM106B immunoreactivity was not confirmed because flortaucipir had a low fluorescence intensity. In vitro binding assays for [¹⁸F]PM-PBB3 and [¹⁸F]flortaucipir demonstrated high affinities for collagenase A-treated choroid plexus homogenate containing transmembrane protein 106B aggregates.

This study demonstrated high affinity of [¹⁸F]PM-PBB3 for TMEM106B aggregates in the choroid plexus. In vivo off-target binding of [¹⁸F]PM-PBB3 to the choroid plexus might result from binding to TMEM106B aggregates.