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

Kathryn M Munro,Jenny M Gunnersen,Stefan F Lichtenthaler,Amelia Nash,Martina Pigoni

doi:10.1007/s12031-016-0800-1

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.

Highlights

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
Given the growing interest in seizure-related gene 6 (Sez6) family proteins as brain is β-site APP-cleaving enzyme 1 (BACE1) substrates, we have provided a comprehensive coverage of the literature below
The lack of reported phenotypes in the single KO mouse lines in this study indicates a level of functional redundancy between Sez6 family members (Miyazaki et al 2006)

Summary

SPECS Secretome protein enrichment with click sugars

Alzheimer’s disease is the most common type of dementia and is characterised pathologically by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles. It is currently unclear how the balance of these two APP peptides will affect the pathological and cognitive changes in Alzheimer’s disease patients In another recent study, Filser et al (2015) chronically treated wild-type mice with a BACE inhibitor and identified altered synaptic morphology and function and behavioural deficits. It will be important to determine whether the BACE1-shed Sez ectodomain performs a similar functional role to the secreted isoform, as effective BACE inhibition would be expected to block ectodomain shedding while enhancing the levels of the intact transmembrane form, as shown in mice (Kuhn et al 2012). To understand how Sez family proteins contribute to the synaptic deficits seen with BACE inhibition, we need to investigate more fully the functions of uncleaved Sez and the BACE1-cleaved Sez ectodomain, and learn more about the roles of Sez6L and Sez6L2 in the adult central nervous system. Conditional L1 KO mice display increased basal excitatory activity in hippocampal CA1 and use different search strategies in the Morris water maze, indicating an alteration in place learning (Law et al 2003)

APP Family

Summary