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P3‐061: TREATMENT OF CELLS EXPRESSING AMYLOID PRECURSOR PROTEIN WITH TAU FIBRILS INDUCES INTRACELLULAR AGGREGATE FORMATION OF TAU
Author(s) -
Takahashi Muneaki,
aka Takashi,
Kametani Fuyuki,
Hisanaga Shinichi,
Hasegawa Masato
Publication year - 2014
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.2014.05.1149
Subject(s) - intracellular , senile plaques , tau protein , fibril , neurodegeneration , extracellular , chemistry , transfection , amyloid precursor protein , microbiology and biotechnology , protein aggregation , p3 peptide , cell culture , amyloid (mycology) , microtubule , biology , alzheimer's disease , biochemistry , pathology , gene , medicine , genetics , inorganic chemistry , disease
over one year post mTBI exposure. We identified a number of candidate OR4M1 ligands based on in silico screening. We screened 25 candidate OR4M1 ligands and identified 2 compounds (Z221560030 and Z154373220) effective in inducing cellular cAMP content in primary neurons with overexpression of OR11M1 from TgOR11M1 transgenic mice. Ongoing studies are exploring the role of OR4M1 ligands in attenuating tau-neuropathology in vitro and in vivo. Conclusions: Our study establish, for the first time, a direct cause-and-effect relationship between blasting mild TBI exposure and long-term down regulation of select ORs and validate our hypothesis that down regulation of select OR in PBMCs and in the brains of our human TBI study cohort may be caused by prior TBI exposure. Data on in silico screening/bioactivity assessments of OR4M1 ligands with improved affinity and specificity for OR4M1 will be presented. The availability of exogenous expressing of OR4M1 mice and high-affinity OR4M1 ligands will allow us to investigate the mechanistic OR4M1 may modulate tau processing.