Pattern of tau hyperphosphorylation and neurotransmitter markers in the brainstem of senescent tau filament forming transgenic mice

Abstract

The early occurrence of brainstem-related symptoms, e.g. gait and balance impairment, apathy and depression in Alzheimer's disease patients suggests brainstem involvement in the initial pathogenesis. To address the question whether tau filament forming mice expressing mutated human tau mirror histopathological changes observed in Alzheimer brainstem, the degree and distribution of neurofibrillary lesions as well as the pattern of cholinergic and monoaminergic neurons were investigated. The expression of the human tau transgene was observed in multiple brainstem nuclei, particularly in the magnocellular reticular formation, vestibular nuclei, cranial nerve motor nuclei, sensory trigeminal nerve nuclei, inferior and superior colliculi, periaqueductal and pontine gray matter, and the red nucleus. Most of the human tau-immunoreactive cell groups also showed tau hyperphosphorylation at the epitopes Thr231/Ser235 and Ser202/Thr205, while abnormal tau phosphorylation at the epitope Ser422 or silver stained structures were almost totally lacking. We found no obvious differences in distribution and density of cholinergic and monoaminergic neurons between tau-transgenic and wild type mice. Although numerous brainstem nuclei in our model expressed human tau protein, the development of neurofibrillary tangles, neuropil threads and ghost tangles was rare and likewise its distribution differed largely from Alzheimer's disease pattern. The number of monoaminergic neurons remained unchanged in the transgenic mice, while monoaminergic nuclei in Alzheimer brainstem showed a distinct neuronal loss. However, the distribution of pretangle-affected neurons in the tau-transgenic mice partly resembled those seen in progressive supranuclear palsy, presenting these animals as a model to examine brainstem pathogenesis of progressive supranuclear palsy.