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P3‐196: DISTINCT CONFORMATIONS, AGGREGATION AND NEURONAL PROPAGATION OF DIFFERENT TAU STRAINS
Author(s) -
Karikari Thomas K.,
Nagel David A.,
Hill Eric J.,
Moffat Kevin G.
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.2018.06.1554
Subject(s) - internalization , alexa fluor , neurite , chemistry , tau protein , protein aggregation , biophysics , intracellular , tauopathy , oligomer , extracellular , circular dichroism , microbiology and biotechnology , biochemistry , cell , neurodegeneration , biology , alzheimer's disease , in vitro , medicine , physics , disease , organic chemistry , pathology , quantum mechanics , fluorescence
cleavage of tau occurs in different dementia patient populations we measured levels ofDtau314 in extracts of inferior temporal gyrus in AD patients, and in PD patients with no cognitive impairment (PDNCI) or dementia (PDD). We obtained these measurements using our newly developed digital immunoassay (HD Simoa, Quanterix), which employs 4F3, a monoclonal antibody that recognizes the neo-epitope created when caspase-2 cleaves tau, to capture Dtau314, and a mixture of BT2/HT7 antibodies to detect Dtau314. Further protein analysis by immunoprecipitation assay were also performed. Results:Our data show a significant increase of Dtau314 in AD patients. In addition, we found higher levels of Dtau314 in PDD (N 1⁄4 21) compared to PD-NCI (N 1⁄4 12) subjects (P1⁄40.0089). PDD patients also had lower levels of soluble total tau (P1⁄40.0005). The Dtau314/total tau ratio was higher in PDD than PD-NCI (P1⁄40.0002). These data support our hypothesis that caspase-2 cleavage of tau contributes to cognitive decline in AD and PDD. Conclusions: Our results show the presence of Dtau314 strongly associates with cognitive deficits in AD and PD. Our cumulative observations link caspase-2 cleavage of tau to processes affecting memory and cognition in AD, PD and FTDP-17. Importantly, these data strengthen the potential of caspase-2 as a novel drug target for multiple neurodegenerative disorders.