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

By Michiyo Iba, Jing L Guo, Jennifer D. McBride, Bin Zhang, John Q. Trojanowski, V. Lee. Journal of Neuroscience, 2013

632 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/29b7bb13d26280f3af3378fe245fab6aa136a2a9

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In Cellular and Molecular Neuroscience

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4. Patrick R. Hof
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Citations in the corpus

• 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.”
• The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans (2019, methodology): “Recombinant P301S human tau fibrils were produced and injected unilaterally into the hippocampus of 8–9 week old P301S male mice, prior to the onset of tau pathology, as described (5).”
• Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [16”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “These aggregates then spread transsynaptically to remote anatomically connected brain regions inducing further seeding and aggregation, similar to the pathologic spread of tau noted in AD brain_(de Calignon et al., 2012; Clavaguera et al., 2009, 2013; Frost et al., 2009; Iba et al., 2013; Liu et al.”
• Depletion of microglia and inhibition of exosome synthesis halt tau propagation (2015, background): “4019), HT7 mouse mAb (specific to hTau, 1:500), T22 rabbit pAb (specific to tau oligomer, 1:500 for dot blot) (5), Tsg101 rabbit pAb (exosomal marker, 1:200, cat.”
• 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.”