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Bace1 activity in cerebrospinal fluid and its relation to markers of ad pathology

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Author: Mulder, S.D. · Flier, W.M. van der · Verheijen, J.H. · Mulder, C. · Scheltens, P. · Blankenstein, M.A. · Hack, C.E. · Veerhuis, R.
Type:article
Date:2010
Institution: TNO Kwaliteit van Leven
Source:Journal of Alzheimer's Disease, 1, 20, 253-260
Identifier: 408460
Keywords: Biology · Biomedical Research · Aβ<sub>-{40}Aβ</sub> · Alzheimer's disease · BACE1 activity · CSF biomarker profile · p-tau · t-tau · {42} · amyloid beta protein[1-40] · amyloid beta protein[1-42] · beta secretase · tau protein · threonine · adult · aged · Alzheimer disease · article · cerebrospinal fluid analysis · clinical article · controlled study · correlational study · enzyme activity · female · human · male · mild cognitive impairment · mini mental state examination · priority journal · protein phosphorylation · Aged · Alzheimer Disease · Amyloid beta-Protein · Amyloid Precursor Protein Secretases · Apolipoproteins E · Aspartic Acid Endopeptidases · Cognition Disorders · Enzyme-Linked Immunosorbent Assay · Female · Humans · Male · Middle Aged · Peptide Fragments · Statistics as Topic · tau Proteins

Abstract

Several studies have shown that reduced amyloid-β 1-42 (Aβ {42}) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. β-site APP cleaving enzyme (BACE1) is thought to be the major β-secretase involved in Aβ production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Aβ {40}, Aβ-{42}, total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n=12), mild cognitive impairment (n=18), and AD (n=17) subjects. Patients were classified according to their Aβ {42}, t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Aβ {42} 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (≤ one biomarker abnormal). This resulted in 19 subjects with an AD-like biomarker profile (66 ± 6 years, 53% female, and Mini-Mental Status Examination (MMSE) score: 23 ± 5) and 28 subjects with a normal biomarker profile (62 ± 11 years, 43% female, and MMSE score: 27 ± 4). Subjects with an AD-like biomarker profile had higher CSF BACE1 activity levels, compared to patients with a normal biomarker profile (20 pg/ml and 16 pg/ml respectively; p=0.01), when controlled for age and gender. In the whole sample, BACE1 activity correlated with CSF levels of Aβ{40}, t-tau, and p-tau (r=0.38, r=0.63, and r=0.65; all p< 0.05), but not with Aβ {42}. These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain. © 2010 - IOS Press and the authors.