Propagation of Tau Pathology in a Model of Early Alzheimer’s Disease

• DOI: 10.1016/j.neuron.2012.10.005
• Publication Date: 2012-10-17T17:18:04Z
• Authors: Alix de Calignon; Manuela Polydoro; Marc Suárez-Calvet; Christopher William; David H. Adamowicz; Kathy J. Kopeikina; Rose Pitstick; Naruhiko Sahara; Karen H. Ashe; George A. Carlson; Tara L. Spires-Jones; Bradley T. Hyman
• Keywords: 0301 basic medicine; Neuroscience(all); tau Proteins; Mice, Transgenic; Hippocampus; Epitopes; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Glial Fibrillary Acidic Protein; Serine; Animals; Entorhinal Cortex; Humans; Gliosis; RNA, Messenger; Neurons; Age Factors; Neurofibrillary Tangles; Mice, Inbred C57BL; Disease Models, Animal; Tauopathies; Gene Expression Regulation; Mutation; Nerve Degeneration; Disease Progression

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.