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Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy

Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2013; 33(3):1024-37. DOI: 10.1523/JNEUROSCI.2642-12.2013
Source: PubMed

ABSTRACT Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathologies, are neurodegenerative diseases characterized by neurofibrillary tangles (NFTs) comprising filamentous tau protein. Although emerging evidence suggests that tau pathology may be transmitted, we demonstrate here that synthetic tau fibrils are sufficient to transmit tau inclusions in a mouse model. Specifically, intracerebral inoculation of young PS19 mice overexpressing mutant human tau (P301S) with synthetic preformed fibrils (pffs) assembled from recombinant full-length tau or truncated tau containing four microtubule binding repeats resulted in rapid induction of NFT-like inclusions that propagated from injected sites to connected brain regions in a time-dependent manner. Interestingly, injection of tau pffs into either hippocampus or striatum together with overlaying cortex gave rise to distinct pattern of spreading. Moreover, unlike tau pathology that spontaneously develops in old PS19 mice, the pff-induced tau inclusions more closely resembled AD NFTs because they were Thioflavin S positive, acetylated, and more resistant to proteinase K digestion. Together, our study demonstrates that synthetic tau pffs alone are capable of inducing authentic NFT-like tau aggregates and initiating spreading of tau pathology in a tauopathy mouse model.

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    • "The cell-to-cell propagation ability is out of the question not only for A␤ and tau as it has been shown in a neural graft transplanted mouse model (Meyer-Luehmann et al., 2003) but also in several animal models where seeding and the propagation ability of those proteins were assessed and the propagation from injection site through neuronal projections was observed (Gotz et al., 2001; Walker et al., 2002; Bolmont et al., 2007; Clavaguera et al., 2009, 2013; Sydow and Mandelkow, 2010; Hurtado et al., 2010; de Calignon et al., 2012; Lasagna-Reeves et al., 2012; Iba et al., 2013). And even in an unusual animal model, tau spreading was shown along human tau expressing Lamprey neurons (Kim et al., 2010). "
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    • "Indeed, it was discovered, that amyloidogenic proteins such as alpha- Synunclein (aSyn), tau, or Abeta can also propagate between cells, and that these transmissible particles share structural properties closely similar to those of the archetypic infectious particle PrP sc : they have a predominant beta-sheet structure, a remarkable resistance against proteolytic and denaturing agents, and a self-templating ability (Prusiner et al., 1983; Luk et al., 2012; Iba et al., 2013; Sanders et al., 2014; Stöhr et al., 2014; Watts et al., 2014). Similar rearrangements are likely to occur for endogenous tau in mice brains upon the stereotactic delivery of toxic tau seeds, which is sufficient to initiate spreading of AD-like neurofibrillary tangles along a spatially defined trajectory (Iba et al., 2013). In close analogy, the injection of aSyn seeds into brains of healthy mice triggers the self-perpetuating polymerization of endogenous aSyn and the development of clinical symptoms of PD (Luk et al., 2012). "
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    • "Clone 9 induced tangle-like inclusions throughout CA1 and CA3, while clone 10 induced AT8-positive puncta in mossy fiber tracts. Here, they show that tau aggregation propagates along known anatomical connections, supporting the conclusions of previous studies (de Calignon et al., 2012; Iba et al., 2013; Liu et al., 2012). However, injected WT mice with these clones never developed pathology, possibly due to a seeding barrier between inoculated tau RD and WT murine tau. "
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