BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology.
Several studies have shown that reduced amyloid-beta 1-42 (Abeta(42)) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. beta-site APP cleaving enzyme (BACE1) is thought to be the major beta-secretase involved in Abeta production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Abeta(40), Abeta(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 Abeta(42), t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Abeta(42) < 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (<or= 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 Abeta(40), t-tau, and p-tau (r=0.38, r=0.63, and r=0.65; all p< 0.05), but not with Abeta(42). These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain.
Mulder
Sandra D
SD
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands. sd.mulder@vumc.nl
van der Flier
Wiesje M
WM
Verheijen
Jan H
JH
Mulder
Cees
C
Scheltens
Philip
P
Blankenstein
Marinus A
MA
Hack
C Erik
CE
Veerhuis
Robert
R
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid*; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D013223:Statistics as Topic; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; C054369:MAPT protein, human; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human