Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

Filip Liebsch, Luka Kulic, Charlotte Teunissen, Adeola Shobo, Irem Ulku, Vivienne Engelschalt, Mark A. Hancock, Wiesje M. van der Flier, Peter Kunach, Pedro Rosa-Neto, Philip Scheltens, Judes Poirier, Paul Saftig, Randall J. Bateman, John Breitner, Christoph Hock, Gerhard Multhaup

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number2240
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019

Cite this

Liebsch, Filip ; Kulic, Luka ; Teunissen, Charlotte ; Shobo, Adeola ; Ulku, Irem ; Engelschalt, Vivienne ; Hancock, Mark A. ; van der Flier, Wiesje M. ; Kunach, Peter ; Rosa-Neto, Pedro ; Scheltens, Philip ; Poirier, Judes ; Saftig, Paul ; Bateman, Randall J. ; Breitner, John ; Hock, Christoph ; Multhaup, Gerhard. / Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression. In: Nature Communications. 2019 ; Vol. 10, No. 1.
@article{e11685650b2a4e189e89f7de730caade,
title = "Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression",
abstract = "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.",
author = "Filip Liebsch and Luka Kulic and Charlotte Teunissen and Adeola Shobo and Irem Ulku and Vivienne Engelschalt and Hancock, {Mark A.} and {van der Flier}, {Wiesje M.} and Peter Kunach and Pedro Rosa-Neto and Philip Scheltens and Judes Poirier and Paul Saftig and Bateman, {Randall J.} and John Breitner and Christoph Hock and Gerhard Multhaup",
year = "2019",
doi = "10.1038/s41467-019-10152-w",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Liebsch, F, Kulic, L, Teunissen, C, Shobo, A, Ulku, I, Engelschalt, V, Hancock, MA, van der Flier, WM, Kunach, P, Rosa-Neto, P, Scheltens, P, Poirier, J, Saftig, P, Bateman, RJ, Breitner, J, Hock, C & Multhaup, G 2019, 'Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression' Nature Communications, vol. 10, no. 1, 2240. https://doi.org/10.1038/s41467-019-10152-w

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression. / Liebsch, Filip; Kulic, Luka; Teunissen, Charlotte; Shobo, Adeola; Ulku, Irem; Engelschalt, Vivienne; Hancock, Mark A.; van der Flier, Wiesje M.; Kunach, Peter; Rosa-Neto, Pedro; Scheltens, Philip; Poirier, Judes; Saftig, Paul; Bateman, Randall J.; Breitner, John; Hock, Christoph; Multhaup, Gerhard.

In: Nature Communications, Vol. 10, No. 1, 2240, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

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

PY - 2019

Y1 - 2019

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 - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066011350&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31110178

U2 - 10.1038/s41467-019-10152-w

DO - 10.1038/s41467-019-10152-w

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2240

ER -