Neuron
Volume 73, Issue 4, 23 February 2012, Pages 685-697
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Article
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease

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Summary

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.

Highlights

► Tau pathology propagates to surrounding mRNA-negative cells (neurons and astrocytes) ► Human tau protein spreads misfolding to downstream synaptically connected areas ► Human tau seeds misfolding of mouse tau ► mRNA-negative DG neurons developed tangles

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These authors contributed equally to this work