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O4‐04‐02: Characterisation of Tau Species Involved in Tau Seeding and Spread in Cellular and Animal Models
Author(s) -
Bose Suchira,
Cavallini Annalisa,
Kerridge Caroline,
Cooper Jane,
Jackson Samuel J.,
Landi Alessia,
Cella Claire V.,
Falcon Benjamin,
Murray Tracey K.,
Ahmed Zeshan,
Goedert Michel,
Hutton Michael,
O'Neill Michael J.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.625
Subject(s) - seeding , tau protein , lysis , tau pathology , intracellular , neuron , biology , biophysics , cell culture , chemistry , biochemistry , microbiology and biotechnology , alzheimer's disease , neuroscience , pathology , genetics , medicine , disease , agronomy
Background:The neurofibrillary tangle is a pathological hallmark of Alzheimer’s disease (AD) and primarily consists of hyperphosphorylated tau protein (pTau). pTau first appears in the entorhinal cortex in the presymptomatic stage, then gradually disseminates to the hippocampal region around the onset of clinical symptoms of AD. Halting this tau spread in the asympomatic stage is a promising therapeutic approach for AD. The exosome is a small vesicle of 50-100 nm in diameter, enriched in ceramide, and is suggested to contain neuropathogenic proteins, such as prion, a-synuclein, and recently tau proteins. A growing body of evidence suggests that microglia contribute to tauopathy-related pathogenesis in both human and animal models. We hypothesize that microglia transduce tau aggregates into nearby neuronal cells via exosomal secretion, and that inhibition of the exosome synthesis or secretory pathway reduces tau dissemination. Methods: Adeno-associated virus serotype 6 expressing FTDP-17-linked mutation of tau protein was stereotaxically injected into the entorhinal cortical region of C57BL/6 mice, and the animals were sacrificed at 7 and 28 days post injection. The brain specimens were examined for tau accumulation in the hippocampal region. The animals were also systemically treated with specific inhibitors of neutral sphingomyelinase-2 to block exosome synthesis, or colony stimulating factor 1 receptor (CSF1R) to deplete microglia. Results:We found that human tau propagate from entorhinal cortical neurons to dentate granular cells after AAV injection, and that this propagation is sensitive to the inhibition of exosome synthesis or microglial depletion. We also found that tau-containing exosomes isolated from microglia efficiently transduce tau protein to neurons in vitro and in vivo. Finally, these results were reproduced in P301S tau mice (PS19) treated with these compounds. Conclusions: These results demonstrate that exosome secretion from microglia play a significant role in propagation of tau protein from entorhinal cortex to hippocampal neurons. Our findings could lead to an entirely novel paradigm for delaying the progression of disease in AD and other tauopathies such as frontotemporal dementia and chronic traumatic encephalopathy.