Wen Hu1, Xinhua Zhang2, Yunn Chyn Tung1, Shutao Xie2, Fei Liu3, Khalid Iqbal4. 1. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. 2. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Jiangsu Key Laboratory of Neuroregeneration and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P.R. China. 3. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Jiangsu Key Laboratory of Neuroregeneration and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P.R. China. Electronic address: feiliu63@hotmail.com. 4. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. Electronic address: khalid.iqbal.ibr@gmail.com.
Abstract
INTRODUCTION: Neurofibrillary pathology of abnormally hyperphosphorylated tau (P-tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission character to tau and produces morphologically distinct tau lesions remains elusive. METHODS: We investigated the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice. RESULTS: We found that intrahippocampal injection with AD P-tau, but not nonphosphorylated tau, produced numerous P-tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain-like morphology. CONCLUSIONS: Our findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight tau hyperphosphorylation as a potential drug target.
INTRODUCTION: Neurofibrillary pathology of abnormally hyperphosphorylatedtau (P-tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission character to tau and produces morphologically distinct tau lesions remains elusive. METHODS: We investigated the role of hyperphosphorylation in the spread of tau pathology in hTautransgenic mice. RESULTS: We found that intrahippocampal injection with AD P-tau, but not nonphosphorylated tau, produced numerous P-tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain-like morphology. CONCLUSIONS: Our findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight tau hyperphosphorylation as a potential drug target.
Authors: Sylvia E Perez; Jennifer C Miguel; Bin He; Michael Malek-Ahmadi; Eric E Abrahamson; Milos D Ikonomovic; Ira Lott; Eric Doran; Melissa J Alldred; Stephen D Ginsberg; Elliott J Mufson Journal: Acta Neuropathol Date: 2019-02-07 Impact factor: 17.088
Authors: Juan Carlos Polanco; Chuanzhou Li; Liviu-Gabriel Bodea; Ramon Martinez-Marmol; Frederic A Meunier; Jürgen Götz Journal: Nat Rev Neurol Date: 2017-12-15 Impact factor: 42.937