Pattern of Tau Hyperphosphorylation in Brainstem Nuclei of Tau Transgenic Mice

Recent reports present evidence for the early appearance of brainstem tau pathology in dementia disorders, such as Alzheimer's disease (AD). Our own preliminary studies revealed neurofibrillary lesions in selected brainstem areas in P301L tau-transgenic pR5 mice. To address the question whether this mouse model mirrors the brainstem changes that are observed in dementia disorders, we investigated the degree and distribution of the tau pathology throughout the brainstem. Coronal brainstem sections of 20-month-old P301L tau transgenic pR5 mice and non-transgenic littermates were screened immunohistochemically for human tau (HT7), the physiologically phosphorylated epitopes Thr231/Ser235 (mAb AT180) and Ser202/Thr205 (mAb AT8), the abnormally phosphorylated epitope Ser422 (mAb pS422) and Gallyas silver-impregnated structures. The expression of the human tau transgene was observed in multiple brainstem nuclei of pR5 mice, particularly in the magnocellular reticular formation, the vestibular nuclei, the cranial nerve motor nuclei, the sensory trigeminal nerve nuclei, the inferior and superior colliculi, the periaqueductal and pontine gray matter, and the red nucleus. Most of the HT7-immunoreactive (ir) nuclei also showed hyperphosphorylation of tau at the epitopes Thr231/Ser235 indicating an early stage of neurofibrillary tangle formation. In comparison to HT7 and AT180, fewer AT8-ir neurons as well as the lack of pS422-positive or silver-stained cell bodies suggests the absence of insoluble filamentous deposits, neuropil threads or ghost tangles. Neither the human tau transgene nor hyperphosphorylated tau protein was detected in brainstem nuclei of non-transgenic littermates. Although numerous brainstem nuclei in P301L tau transgenic pR5 mice express human tau protein, the development of neurofibrillary lesions seems to be rare, whereas human tissue shows severe affection of brainstem nuclei in early stages of AD. The pattern of tau pathology throughout the brainstem of pR5 mice differs largely from AD, while the distribution of affected nuclei partly resembles those seen in other tauopathies, particularly in progressive supranuclear palsy (PSP). Therefore the brainstem of pR5 mice might be a suitable system to examine pathogenic mechanisms in PSP.