Increased Plasma TACE Activity in Subjects with Mild Cognitive Impairment and Patients with Alzheimer's Disease

Article type: Research Article

Authors: Sun, Qiying^{a; f} | Hampel, Harald^{b; d} | Blennow, Kaj^c | Lista, Simone^d | Levey, Allan^e | Tang, Beisha^f | Li, Rena^{f; g; *} | Shen, Yong^{a; f; h; *}

Affiliations: [a] Center for Advanced Therapeutic Strategies for Brain Disorders, The Roskamp Institute, Sarasota, FL, USA | [b] Department of Psychiatry and Psychotherapy, Alzheimer Memorial Center, University of Munich, Munich, Germany | [c] Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Sahlgren's University Hospital, Mölndal, Sweden | [d] Université Pierre et Marie Curie, Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Salpêtrière, Paris, France | [e] Department of Neurology and Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA | [f] Department of Neurology, Xiangya Hospital, Central South University, Changsha, China | [g] Center for Hormone Advanced Science and Education, Roskamp Institute, Sarasota, FL, USA | [h] Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA

Correspondence: [*] Correspondence to: Dr. Yong Shen and Dr. Rena Li, Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. E-mails: yshen@rfdn.org (Yong Shen); rli@rfdn.org (Rena Li).

Abstract: Evidence suggests that the tumor necrosis factor receptor (TNFR)-signaling pathway contributes to the pathogenesis of Alzheimer's disease (AD). TNF-α converting enzyme (TACE/ADAM-17) can cleave both pro-TNF-α and TNF receptors. Recently, we have shown that TACE activity in the cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI) and AD patients is significantly higher than that of cognitively healthy controls (HC). To date, it is not clear whether TACE activity could be detected in the human plasma and whether TACE activity in MCI and AD patients is different from that in HC. We analyzed TACE expression and activity in a large clinical sample of 64 patients with AD, 88 subjects with MCI, and 50 age-matched HC recruited from two distinct academic centers. Plasma TACE protein levels did not differ significantly in the three study groups (AD, MCI, and HC). However, plasma TACE activity in subjects with MCI and AD patients was significantly higher than that in HC. Moreover, in MCI and AD groups, we found a significant correlation between plasma TACE activity and CSF t-tau and Aβ42 levels and CSF Aβ42/tau ratios. In AD patients, the levels of plasma TACE activity correlated significantly and negatively with cognition. These findings further support the role of the TNF-α receptor complex in AD-related neuroinflammation and propose TACE plasma activity as a promising hypothesis-driven biomarker candidate for detection, diagnosis, and prognosis of prodromal and clinical AD.

Keywords: Alzheimer's disease, biomarker, mild cognitive impairment, plasma, tumor necrosis factor converting enzyme

DOI: 10.3233/JAD-140177

Journal: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 877-886, 2014