Your search for: 'author:("Sankaranarayanan, Sethu")' has returned 2 results. (0.007s) Save search

Authors: Barten, Donna M. | Cadelina, Gregory W. | Hoque, Nina | DeCarr, Lynn B. | Guss, Valerie L. | Yang, Ling | Sankaranarayanan, Sethu | Wes, Paul D. | Flynn, Marianne E. | Meredith, Jere E. | Ahlijanian, Michael K. | Albright, Charles F.

Article Type: Research Article

Abstract: Levels of tau in cerebrospinal fluid (CSF) are elevated in Alzheimer's disease (AD) patients. It is believed this elevation is related to the tau pathology and neurodegeneration observed in AD, but not all tauopathies have increased CSF tau. There has been little pre-clinical work to investigate mechanisms of increased CSF tau due to the difficulty in collecting CSF samples from mice, the most commonly used pre-clinical models. We developed methods to collect CSF from mice without contamination from tau in brain tissue, which is approximately 50,000 fold more abundant in brain than CSF. Using these methods, we measured CSF tau …from 3xTg, Tg4510, and Tau Alone transgenic mice. All three lines of mice showed age-dependent increases in CSF tau. They varied in phenotype from undetectable to severe tau pathology and neurodegeneration, suggesting that degenerating neurons are unlikely to be the only source of pathologic CSF tau. Overall, CSF tau levels mirrored expression levels and changes of tau in the brain, but they did not always correlate exactly. CSF tau was often more sensitive to changes in brain transgene expression and pathology. In addition, we also developed ELISA assays specific to different regions of the tau protein. We used these assays to provide evidence that CSF tau exists as fragments, with little intact C-terminus and partial loss of the N-terminus. Taken together, these assays and mouse models may be used to facilitate a deeper understanding of CSF tau in neurodegenerative disease. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, ELISA, FTDP-17 protein, human, MAPT, mice, tau proteins, tauopathy, transgenic

DOI: 10.3233/JAD-2011-110161

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 127-141, 2011

Authors: Shi, Xiao-Ping | Tugusheva, Katherine | Bruce, James E. | Lucka, Adam | Chen-Dodson, Elizabeth | Hu, Binghua | Wu, Guo-Xin | Price, Eric | Register, Robert B. | Lineberger, Janet | Miller, Ron | Tang, Mei-Jy | Espeseth, Amy | Kahana, Jason | Wolfe, Abigail | Crouthamel, Ming-Chih | Sankaranarayanan, Sethu | Simon, Adam | Chen, Lin | Lai, Ming-Tain | Pietrak, Beth | DiMuzio, Jillian | Li, Yueming | Xu, Min | Huang, Qian | Garsky, Victor | Sardana, Mohinder K. | Hazuda, Daria J.

Article Type: Research Article

Abstract: Abnormal production and accumulation of amyloid-β peptide (Aβ) plays a major role in the pathogenesis of Alzheimer's disease (AD). β-secretase (BACE1) is responsible for the cleavage at the β-site in amyloid β protein precursor (AβPP/APP) to generate the N-terminus of Aβ. Here we report the stepwise identification and characterization of a novel APP-β-site mutant, “NFEV” (APP_NFEV) in vitro and in cells. In vitro, the APP_NFEV exhibits 100-fold enhanced cleavage rate relative to the “wild-type” substrate (APPwt) and 10-fold increase relative to the Swedish-type mutation variant (APPsw). In cells, it was preferably cleaved among 24 APP β-site mutations tested. More importantly, …the APP_NFEV mutant failed to generate any detectable Aβ peptides in BACE1-KO mouse fibroblast cells. The production of Aβ peptides was restored by co-transfecting human BACE1, demonstrating that BACE1 is the only enzyme responsible for the processing of APP_NFEV in these cells. Analysis of APP_NFEV cleavage products secreted in the media revealed that in cells BACE1 cleaves APP_NFEV at the position between NF and EV, identical to that observed in vitro. A BACE inhibitor blocked the processing of the APP_NFEV β-site in vitro and in cells. Our data indicates that the "NFEV" mutant is not only an enhanced substrate for BACE1 in vitro, but also a specific substrate for BACE1 in cells. Show more

Keywords: Alzheimer's disease, BACE, β-secretases, APP

DOI: 10.3233/JAD-2005-7207

Citation: Journal of Alzheimer's Disease, vol. 7, no. 2, pp. 139-148, 2005