Interneuronal Transfer of Human Tau Between Lamprey Central Neurons in situ

Department of Biological Sciences, Center for Cellular Neuroscience and Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 19(2):647-64. DOI: 10.3233/JAD-2010-1273
Source: PubMed


The mechanisms by which tau-containing lesions are propagated between adjacent and synaptically interconnected parts of the brain are a potentially important but poorly understood component of human tauopathies such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Since the utility of currently available transgenic models for studying intercellular aspects of tauopathy is limited by their broad patterns of tau expression in the central nervous system, we used an in situ tauopathy model that replicates tau-induced cytodegeneration in identified neurons on a tau-negative background to determine whether tau secretion or interneuronal transfer might play a role in lesion propagation. We found that the N-terminal half of tau is required for tau secretion and is efficiently exported to the extracellular space and adjacent neurons at relatively low levels of overexpression. By contrast, full-length tau is secreted by a separate mechanism that is correlated with phosphorylation of tau at tyrosine 18 and dendritic degeneration, is exacerbated by tauopathy mutations, and blocked by mutations that inhibit tau:tau interactions. Anterograde transneuronal tau movement occurred with the expression of tau containing the P301L tauopathy mutant, but not with wild type tau isoforms. Our results are consistent with recent studies suggesting a role for molecular "templating" in the propagation of neurofibrillary lesions and provide a novel conceptual and experimental basis for studying the mechanisms of interneuronal propagation and toxicity in human neurodegenerative disease.

Download full-text


Available from: Garth F. Hall,
  • 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). In particular, some studies focus on propagation mechanisms paying special attention, for instance, to the temporal progression of A␤ plaque accumulation in animal models showing that it starts with intracellular deposits in certain brain areas that slowly progress to extracellular inclusions possibly derived from 'leaking' neurons that eventually spread to most of the brain (Leon 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; 207. DOI:10.1016/j.virusres.2015.04.014 · 2.32 Impact Factor
  • Source
    • "This implies that NFTs would propagate in the brain by the release of misfolded tau aggregates from an affected neuron followed by its uptake in neighboring neurons. Consistent with this, recent studies, including our own demonstrated that tau can be secreted and endocytosed both in vitro and in vivo9101112131415161718192021. Most interestingly, in a transgenic mouse model where human tau overexpression was restricted to the entorhinal cortex, the first region to be affected in AD, the spreading of tau pathology was observed along synaptically connected circuits2223. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain.
    Scientific Reports 07/2014; 4:5715. DOI:10.1038/srep05715 · 5.58 Impact Factor
  • Source
    • "We performed our study using differentiated primary cultures and adult rat that both express the six Tau isoforms (data not shown and [36]). One study shows that Tau secretion is specifically inhibited by the presence of the exon 2 in transfected neuronal lines [65]. Nevertheless, the influence of exon 2 is still debated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
    PLoS ONE 06/2014; 9(6):e100760. DOI:10.1371/journal.pone.0100760 · 3.23 Impact Factor
Show more