Title | Propagation of tau pathology in a model of early Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | de Calignon, A, Polydoro, M, Suárez-Calvet, M, William, C, Adamowicz, DH, Kopeikina, KJ, Pitstick, R, Sahara, N, Ashe, KH, Carlson, GA, Spires-Jones, TL, Hyman, BT |
Journal | Neuron |
Volume | 73 |
Issue | 4 |
Pagination | 685-97 |
Date Published | 2012 Feb 23 |
ISSN | 1097-4199 |
Keywords | Age Factors, Alzheimer Disease, Animals, Disease Models, Animal, Disease Progression, Entorhinal Cortex, Epitopes, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Gliosis, Hippocampus, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Degeneration, Neurofibrillary Tangles, Neurons, RNA, Messenger, Serine, tau Proteins, Tauopathies |
Abstract | Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration. |
DOI | 10.1016/j.neuron.2011.11.033 |
Alternate Journal | Neuron |
PubMed ID | 22365544 |
PubMed Central ID | PMC3292759 |
Grant List | AG026249 / AG / NIA NIH HHS / United States AG08487 / AG / NIA NIH HHS / United States K08 NS069811 / NS / NINDS NIH HHS / United States K08NS069811 / NS / NINDS NIH HHS / United States K99AG33670 / AG / NIA NIH HHS / United States R00 AG033670 / AG / NIA NIH HHS / United States R01 AG008487 / AG / NIA NIH HHS / United States R01 AG008487-20 / AG / NIA NIH HHS / United States R01 AG026249 / AG / NIA NIH HHS / United States R01 AG026249-08 / AG / NIA NIH HHS / United States R21 AG038835 / AG / NIA NIH HHS / United States R21 AG038835-01A1 / AG / NIA NIH HHS / United States R21 AG038835-02 / AG / NIA NIH HHS / United States R21 NS067127 / NS / NINDS NIH HHS / United States R21AG038835-01A1 / AG / NIA NIH HHS / United States |
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