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.

  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 04/2015; DOI:10.1016/j.virusres.2015.04.014
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many neurodegenerative disorders are linked to irreversible protein aggregation, a process that usually comes along with toxicity and serious cellular damage. However, it is emerging that protein aggregation can also serve for physiological purposes, as impressively shown for prions. While the aggregation of this protein family was initially considered exclusively toxic in mammalians organisms, it is now almost clear that many other proteins adopt prion-like attributes to rationally polymerize into higher order complexes with organized physiologic roles. This implies that cells can tolerate at least in some measure the accumulation of inherently dangerous protein aggregates for functional profit. This review summarizes currently known strategies that living organisms adopt to preserve beneficial aggregation, and to prevent the catastrophic accumulation of toxic aggregates that frequently accompany neurodegeneration.
    Frontiers in Cellular Neuroscience 02/2015; 9. DOI:10.3389/fncel.2015.00045
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014. Published by Elsevier B.V.
    Virus Research 10/2014; DOI:10.1016/j.virusres.2014.10.020
Show more