Localization of AD biomarker phospho-tau proteins in the brains of an App knock-in mouse model of Aβ amyloidosis.

Abstract

Amyloid-β (Aβ) plaques, neurofibrillary tangles composed of hyper-phosphorylated tau proteins and neurodegeneration are neuropathological hallmarks of Alzheimer's disease (AD). Recently, phospho-tau proteins in blood as well as cerebrospinal fluid have been reported as promising biomarkers in the preclinical stage of AD. However, physiological and pathological roles of these phosphorylated tau proteins in AD pathogenesis remain elusive. In this study, we investigated the localization of AD biomarker phospho-tau proteins in the brains of App knock-in (App NLGF ) mouse, which is thought to mimic important aspects in the early phase of AD. To investigate the localization of AD biomarker phospho-tau proteins in the brains of aged (24- month-old) App NLGF and wild-type mice, we prepared frozen brain sections and co-immunostained with phospho-tau specific antibodies and reactive gliosis or synaptic marker antibodies. We found that one AD biomarker phospho-tau signals were detected in the axonal structures in the brains of wild-type mice, and these structures were disrupted in the brains of App NLGF mice. In contrast, the other AD biomarker phospho-tau epitopes were only detected in the brains of App NLGF mice as punctate signals around Aβ plaques. These phospho-tau signals were co-localized with post-synaptic marker PSD95, but not with reactive gliosis or pre-synaptic markers. Our results suggest that AD biomarker phospho-tau epitopes may represent axonal degeneration or Aβ plaque-related post-synaptic pathology in the early phase of AD brains.