title: Propagation of tau pathology in a model of early Alzheimer's disease.
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.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Alix
authors.initials: A
authors.lastname: de Calignon
authors.forename: Manuela
authors.initials: M
authors.lastname: Polydoro
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.forename: Christopher
authors.initials: C
authors.lastname: William
authors.forename: David H
authors.initials: DH
authors.lastname: Adamowicz
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Kopeikina
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.forename: Karen H
authors.initials: KH
authors.lastname: Ashe
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology*; D000939:Epitopes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000939:Epitopes; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D016875:tau Proteins; D012694:Serine