Trans-Synaptic Spread of Tau Pathology In Vivo

By Li Liu, Valérie Drouet, Jessica W. Wu, Menno P. Witter, Scott A. Small, Catherine L. Clelland, K. Duff. PLoS ONE, 2012

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Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10–11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/022b2227c90d9d9ac4d39d3db7677be3eccb0469

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Citations in the corpus

Physiological release of endogenous tau is stimulated by neuronal activity (2013, neutral): “However, in two lines of transgenic mice overexpressing a single isoform of mutant tau (P301L), known to cause fronto-temporal dementia, inter-neuronal transfer of mutant tau appears to occur before any marked neurodegeneration [5,6].”
Distinct tau prion strains propagate in cells and mice and define different tauopathies (2014, background): “In vivo work supports this model (Clavaguera et al., 2009; de Calignon et al., 2012; Iba et al., 2013; Kim et al., 2010; Liu et al., 2012) as has similar work with other intracellular amyloids such as a-synuclein (Desplats et al.”
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein (2015, positive): “A substantial species barrier was not present because human mutant tau seeds were reported to induce aggregation of wild-type murine tau (82, 83).”
Neuronal activity enhances tau propagation and tau pathology in vivo (2016, methodology): “(g) Significant difference was found in in tau released after stimulation (30 min; n = 4 cultures per condition; Kruskal-Wallis χ(2)(2) = 7.”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “In transgenic mouse models exclusively expressing human tau P301L in the EC region, pathological human tau spreads to synaptically connected regions such as dentate gyrus of the hippocampus, and induces synaptic degeneration with aging [236, 237].”
Brain homogenates from human tauopathies induce tau inclusions in mouse brain (2013, result): “The present findings also show that aggregates made of human tau can induce the formation of inclusions made of mouse tau, in line with recent findings (24, 25).”
PET Imaging of Tau Deposition in the Aging Human Brain (2016, neutral): “…and transgenic mouse models suggest that tau in its harmful hyperphosphorylated form spreads from entorhinal cortex, likely in a trans-synaptic manner, along functional networks and disrupts them, eventually causing neurodegeneration (Fox et al., 2011; Liu et al., 2012; Menkes-Caspi et al., 2015).”
Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds (2013, background): “(2007) beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.”
Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer’s-like Tauopathy (2013, background): “…Clavaguera et al. (2009) showed that diseased mouse brain lysates containing pathological tau induce spread of tau pathology in recipient mice and Liu et al. (2012) and de Calignon et al. (2012) demonstrated trans-synaptic spreading of tau pathology in mouse brains, the nature of tau species…”