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Cell Rep. 2017 Jun 6;19(10):1967-1976. doi: 10.1016/j.celrep.2017.05.034.

The Alzheimer's Disease γ-Secretase Generates Higher 42:40 Ratios for β-Amyloid Than for p3 Peptides.

Author information

1
Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren Campus, 8952 Schlieren, Switzerland. Electronic address: gabriele.siegel@irem.uzh.ch.
2
Foundation Eclosion, 1228 Plan-les-Ouates & Campus Biotech Innovation Park, 1202 Geneva, Switzerland; Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland; Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
3
Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty, 53127 Bonn, Germany; LIFE & BRAIN GmbH, 53127 Bonn, Germany.
4
Foundation Eclosion, 1228 Plan-les-Ouates & Campus Biotech Innovation Park, 1202 Geneva, Switzerland; Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland.
5
Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren Campus, 8952 Schlieren, Switzerland. Electronic address: rajendran@bli.uzh.ch.

Abstract

Alzheimer's disease is characterized by intracerebral deposition of β-amyloid (Aβ). While Aβ40 is the most abundant form, neurotoxicity is mainly mediated by Aβ42. Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases gives rise to full-length Aβ (Aβ1-x) and N-terminally truncated Aβ' (Aβ11-x) whereas cleavage by α- and γ-secretases leads to the shorter p3 peptides (Aβ17-x). We uncovered significantly higher ratios of 42- versus 40-ending variants for Aβ and Aβ' than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free γ-secretase assay with recombinant APP-CTFs. The 42:40 ratio was highest for Aβ', followed by Aβ and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by γ-secretase already at the ε-cleavage stage. This mechanistic insight could aid in developing substrate-targeted modulators of APP-C99 processing to specifically lower the Aβ42:Aβ40 ratio without compromising γ-secretase function.

KEYWORDS:

AICD; APP CTF; Alzheimer’s disease; amyloid precursor protein; amyloidogenic pathway; beta-Amyloid; gamma-secretase; iPS cells; p3 peptide; primary neurons

PMID:
28591569
DOI:
10.1016/j.celrep.2017.05.034
[Indexed for MEDLINE]
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