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O4‐05‐05: PREVENTION OF TAU SEEDING AND SPREADING IN TRANSGENIC MOUSE MODELS BASED ON INTRACRANIAL‐INJECTION OF P301L‐K18 FIBRILS OR ALZHEIMER'S DISEASE LYSATE BY PASSIVE IMMUNOTHERAPY
Author(s) -
Albert Marie,
Caillierez Raphaelle,
Danis Clément,
Lieger Sarah,
Bégard Séverine,
Mairet-Coello Georges,
Courade Jean-Philippe,
Citron Martin,
Buee Luc,
Colin Morvane
Publication year - 2018
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.2018.06.2937
Subject(s) - tauopathy , tau pathology , tau protein , transgene , genetically modified mouse , hippocampus , pathology , antibody , intracellular , immunotherapy , in vivo , biology , neuroscience , chemistry , microbiology and biotechnology , medicine , immunology , alzheimer's disease , disease , neurodegeneration , biochemistry , immune system , genetics , gene
and potently inhibitedDYRK1a kinase activity (IC501⁄4 2nM). In cells, SM07883 reduced pTau at the Threonine 212 site (EC501⁄4 16nM). In pharmacokinetic studies, SM07883 demonstrated good exposure across multiple species (mouse brain : plasma ratio > 3). Compared to vehicle,WTmice showed a dose dependent reduction of transiently induced brain pTau in a pharmacodynamic model starting with a single, 1.25mg/kg SM07883 dose (47%, p1⁄40.0002). JNPL3mice treated with SM07883 demonstrated significant (p<0.05) reductions in Tau hyperphosphorylation, oligomeric and aggregated Tau, and significantly lowerNFTstainingcompared tovehicle.ReducedGFAPimmunoreactivity was confirmed by Western Blotting (37%, p1⁄40.0010). SM07883 was well tolerated with weight gain over the 3 month treatment period and reduced morbidity and mortality in treated animals compared to vehicle. Motor function in the wire hanging test was significantly improved in SM07883-treated JNPL3 mice compared to vehicle (p1⁄40.034) starting 5 weeks after treatment initiation. Conclusions: SM07883, a selective and potent, oral, brain-penetrant, DYRK1a inhibitor significantly reduced Tau phosphorylation, the effects of pathological Tau overexpression, and neuroinflammation, and improved functional endpoints compared to vehicle. SM07883 has potential as a treatment for chronic tauopathies such as AD.