TY - JOUR
T1 - Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression
AU - Liebsch, Filip
AU - Kulic, Luka
AU - Teunissen, Charlotte
AU - Shobo, Adeola
AU - Ulku, Irem
AU - Engelschalt, Vivienne
AU - Hancock, Mark A.
AU - van der Flier, Wiesje M.
AU - Kunach, Peter
AU - Rosa-Neto, Pedro
AU - Scheltens, Philip
AU - Poirier, Judes
AU - Saftig, Paul
AU - Bateman, Randall J.
AU - Breitner, John
AU - Hock, Christoph
AU - Multhaup, Gerhard
N1 - Funding Information:
Thanks to Robert Umek and Martin Boissonneault (Meso Scale Discovery) for their help and support with the electrochemiluminescence assay development, to Konrad Beyr-euther and Chris Weise for discussions, as well as Peter Kang and Arthuro Aliaga for technical support with the rat experiments. We thank Johan Lundkvist for providing us with Fc-BACE1 and discussions. We thank the PREVENT-AD group (public-private partnership using funds provided by McGill University, the Fonds de Recherche du Québec – Santé (FRQ-S), an unrestricted research grant from Pfizer Canada, the Lev-esque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation). The Founding Director of the program is John C. S. Breitner, MD, MPH, Douglas Hospital Research Centre and Faculty of Medicine, McGill University, Montréal, QC, Canada. Program CoDirectors include Associate Directors Judes Poirier, PhD, and Pierre Etienne, MD, and Deputy Director Pedro Rosa-Neto, MD, PhD, all at the same institutions. For up-to-date information, see http://www.preventalzheimer.ca. Thanks to Brain@McGill, the Velux Stiftung, the Natural Sciences and Engineering Research Council of Canada, the Canadian Consortium on Neurodegeneration in Aging, and the Canadian Institute of Health Research (MOP-133411) for support awarded to G.M, C.H., L.K., or F.L. Thanks to the Studienstiftung des Deutschen Volkes, and the Groupe de Recherche Axé sur la Structure des Protéines (GRASP, McGill University) for Ph.D. fellowships awarded to F.L., and the DFG (SFB877-TPA3) for funding awarded to P.S. G.M. holds both a Canada Research Chair in Molecular Pharmacology and a Canada Foundation for Innovation (CFI) grant. The McGill SPR-MS Facility thanks the CFI for infrastructure support.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.
AB - The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.
UR - http://www.scopus.com/inward/record.url?scp=85066011350&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10152-w
DO - 10.1038/s41467-019-10152-w
M3 - Article
C2 - 31110178
AN - SCOPUS:85066011350
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2240
ER -