Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in aging mice

Summary

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of the THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells, but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity, but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

Graphical abstract

Highlights

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  Human Tau spreads from pyramidal cell axons to oligodendrocytes in THY-Tau22 mice

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  Aged transgenic mice have fewer high-firing prosubicular pyramidal neurons

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  THY-Tau22 mice show reduced short-term familiarity in spatial memory tasks

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  Despite extensive Tau load, network oscillations and firing patterns are maintained

Abstract

Viney et al. find that pathological human Tau proteins in a mouse model spread from affected pyramidal neurons to the oligodendrocytes insulating their axons. Over the lifespan, human Tau causes neurodegeneration and a selective loss of a high-firing pyramidal cell population, but network activity is maintained by unaffected brain areas.