Journal Article

DZNE-2020-04740

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

Ben Halima, S. ; Mishra, S. ; Raja, K. M. P. ; Willem, M. ; Baici, A. ; Simons, K. ; Brüstle, O.DZNE* ; Koch, P. ; Haass, C.DZNE* ; Caflisch, A. ; Rajendran, L. (Corresponding author)

2016
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2016.01.076

Abstract: Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

Keyword(s): Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: enzymology (MeSH) ; Amyloid Precursor Protein Secretases: antagonists & inhibitors (MeSH) ; Amyloid Precursor Protein Secretases: chemistry (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Amyloid beta-Protein Precursor: chemistry (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: chemistry (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Cells, Cultured (MeSH) ; Endocytosis (MeSH) ; Endosomes: metabolism (MeSH) ; Golgi Apparatus: metabolism (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells (MeSH) ; Kinetics (MeSH) ; Mice (MeSH) ; Molecular Dynamics Simulation (MeSH) ; Neuregulin-1: chemistry (MeSH) ; Neuregulin-1: metabolism (MeSH) ; Oligopeptides: chemistry (MeSH) ; Oligopeptides: pharmacology (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Protein Transport (MeSH) ; Proteolysis (MeSH) ; Substrate Specificity (MeSH) ; Amyloid beta-Protein Precursor ; NRG1 protein, human ; Neuregulin-1 ; OM99-2 ; Oligopeptides ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; BACE1 protein, human

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Contributing Institute(s):

1. Cell Programming Unit (Cell Programming Unit)
2. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2016

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; DOAJ Seal ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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