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J Mol Neurosci. 2016 Nov;60(3):305-315. Epub 2016 Jul 25.

Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System.

Author information

1
Department of Anatomy and Neuroscience, School of Biomedical Sciences, The University of Melbourne, Parkville, Melbourne, Australia. kathryn.munro@unimelb.edu.au.
2
Department of Anatomy and Neuroscience, School of Biomedical Sciences, The University of Melbourne, Parkville, Melbourne, Australia.
3
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
4
Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technische Universität München, 81675, Munich, Germany.
5
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Abstract

Inhibition of the protease β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a promising treatment strategy for Alzheimer's disease, and a number of BACE inhibitors are currently progressing through clinical trials. The strategy aims to decrease production of amyloid-β (Aβ) peptide from the amyloid precursor protein (APP), thus reducing or preventing Aβ toxicity. Over the last decade, it has become clear that BACE1 proteolytically cleaves a number of substrates in addition to APP. These substrates are not known to be involved in the pathogenesis of Alzheimer's disease but have other roles in the developing and/or mature central nervous system. Consequently, BACE inhibition and knockout in mice results in synaptic and other neuronal dysfunctions and the key substrates responsible for these deficits are still being elucidated. Of the BACE1 substrates that have been validated to date, a number may contribute to the synaptic deficits seen with BACE blockade, including neuregulin 1, close homologue of L1 and seizure-related gene 6. It is important to understand the impact that BACE blockade may have on these substrates and other proteins detected in substrate screens and, if necessary, develop substrate-selective BACE inhibitors.

KEYWORDS:

Alzheimer’s disease; BACE inhibitors; BACE1; Sez6; Synapse

PMID:
27456313
PMCID:
PMC5059407
DOI:
10.1007/s12031-016-0800-1
[Indexed for MEDLINE]
Free PMC Article

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