Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment

• Type of Material: Article
• Authors: Yong Shen, University of Science & Technology of China; Haibo Wang, Roskamp Institute; Qiying Sun, Roskamp Institute; Hailan Yao, Roskamp Institute; Andrew P Keegan, Roskamp Institute; Mike Mullan, Roskamp Institute; Jeffrey Wilson, Arizona State University; Simone Lista, Pitie Salpetriere University Hospital; Thomas Leyhe, University Hospital of Tübingen; Christoph Laske, University Hospital of Tübingen; Dan Rujescu, Ludwig-Maximilian University; Allan Levey, Emory University; Anders Wallin, University of Gothenburg; Kaj Blennow, University of Gothenburg; Rena Li, Capital Medical University; Harald Hampel, Pitie Salpetriere University Hospital
• Language: English
• Date: 2018-03-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Society of Biological Psychiatry
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2017.02.007
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 83
• Issue: 5
• Start Page: 447
• End Page: 455
• Grant/Funding Information: The research leading to these results has received funding from the program “Investissements d’avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6) (HH).; This work was supported by the National Key Research and Development Program, Ministry of Science and Technology of China 2016YFC1300500-03 (YS), the National Institute on Aging (NIHR01AG032441-01, YS, NIHR21 AG049237, RL and RO1AG025888, YS); Alzheimer’s Association (Zenith Award and IIRG-07-59510, YS); the American Health Assistance Foundation (G2006-118, RL); HH is supported by the AXA Research Fund, the Fondation Université Pierre et Marie Curie and the Fondation pour la Recherche sur Alzheimer, Paris, France. Ce travail a beneficie d’une aide de l’Etat «Investissements d’avenir » ANR-10-IAIHU-06 (HH).
• Keywords: INHIBITORS; MUTATION; Alzheimer's disease dementia; AMYLOID PRECURSOR PROTEIN; Life Sciences & Biomedicine; BACE1; PUNCTURE HEADACHE; Biomarker diagnosis; BACE1 ACTIVITY; Neurosciences & Neurology; Mild cognitive impairment; REDUCTION; BIOMARKERS; Science & Technology; EXPRESSION; Prediction; beta-secretase; Neurosciences; Psychiatry; DESIGN; CEREBROSPINAL-FLUID
• Research Categories: Psychology, Cognitive; Biology, Neuroscience; Biology, Physiology

Abstract

Background: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. Methods: Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. Results: Compared with healthy control subjects, plasma BACE1 activity (V max ) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. Conclusions: Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.