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Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease
Authors:Hong Jiang  Harald Hampel  David Prvulovic  Anders Wallin  Kaj Blennow  Rena Li  Yong Shen
Institution:5. Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ, 85351, USA
6. Current address: State Key disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
2. Department of Psychiatry, Psychosomatic Medicine & Psychotherapy, Goethe University, Frankfurt, Germany
3. Department of Clinical Neuroscience, University of G?teborg, Sahlgren’s University Hospital, M?lndal, Sweden
4. Center for Hormone Advanced Science and Education Roskamp Institute, Sarasota, FL, 34243, USA
1. Center for Advanced Therapeutic Strategies for Brain Disorders, Roskamp Institute, Sarasota, FL, 34243, USA
Abstract:We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
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