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

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

Research output: Contribution to journalArticlepeer-review

804 Scopus citations

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. Alzheimer's tangles occur in anatomically connected regions. de Calignon et al. expressed tauP301L exclusively in mouse entorhinal cortex and found that with age, tangles occur both locally and in entorhinal projection targets, suggesting that tau may propagate across synapses.

Original languageEnglish (US)
Pages (from-to)685-697
Number of pages13
JournalNeuron
Volume73
Issue number4
DOIs
StatePublished - Feb 23 2012

Bibliographical note

Funding Information:
This work was supported by an Alzheimer's Association Zenith award; National Institutes of Health grants AG08487, AG026249, K08NS069811, K99AG33670, R21AG038835-01A1, and R21 NS067127; and American Health Assistance Foundation grant A2011086. We thank Mark Mayford for providing neuropsin-tTA mice, Peter Davies for providing tau antibodies, and Zhanyun Fan, Taylor Friedman, Charles Vanderburg, Ozge Cagsal-Getkin, and Meredith Banigan for technical assistance.

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