BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines.

Tanja Blume,Anna Jaworska,Stefan F Lichtenthaler,Gerhard Koenig,Jean-Francois Blain,Katrin Moschke,Jochen Herms,Severin Filser

doi:10.3389/fnagi.2018.00229

Abstract

Beta-site amyloid-precursor-protein cleaving enzyme 1 (BACE1) is the rate limiting protease in the production of the amyloid-beta peptide (Aβ), which is considered to be the causative agent in the pathogenesis of Alzheimer’s Disease (AD). Therefore, the therapeutic potential of pharmacological BACE1 inhibitors is currently tested in clinical trials for AD treatment. To ensure a positive clinical outcome it is crucial to identify and evaluate adverse effects associated with BACE1 inhibition. Preclinical studies show that chronic blockade of BACE1 activity alters synaptic functions and leads to loss of dendritic spines. To assess the mechanism of synapse loss, dendritic spine dynamics of pyramidal layer V cells were monitored by in vivo two-photon microscopy in the somatosensory cortex of mice, treated with the BACE1 inhibitor MK-8931. MK-8931 treatment significantly reduced levels of Aβ40 and density of dendritic spines in the brain. However, the steady decline in dendritic spine density specifically resulted from a diminished formation of new spines and not from a loss of stable spines. Furthermore, the described effects on spine formation were transient and recovered after inhibitor withdrawal. Since MK-8931 inhibition did not completely abolish spine formation, our findings suggest that carefully dosed inhibitors might be therapeutically effective without affecting the structural integrity of excitatory synapses if given at an early disease stage.

Highlights

Beta-site amyloid-precursor-protein cleaving enzyme 1 (BACE1) is considered as a potential drug target for therapeutic intervention in Alzheimer’s disease (AD) for years
Chronic treatment with 12 and 40 mg/kg MK-8931 resulted in a dose-dependent reduction in cerebrospinal fluid (CSF) Aβ levels after 12 h, of 40% and 80% respectively, in mild-to-moderate AD patients (Forman et al, 2013; Andrew Stamford, 2015) and in the transgenic AD mouse model Tg2576 (Villarreal et al, 2017)
Prior studies with two different BACE1 inhibitors showed a significant decrease in the fraction of newly gained spines, implicating an important role for BACE1 in promoting dendritic spine development (Filser et al, 2015)

Summary

INTRODUCTION

Beta-site amyloid-precursor-protein cleaving enzyme 1 (BACE1) is considered as a potential drug target for therapeutic intervention in Alzheimer’s disease (AD) for years. It has been shown that BACE1 inhibition efficiently lowers Aβ levels in the central nervous system of healthy subjects and AD patients (Forman et al, 2012; Neumann et al, 2015; Thakker et al, 2015; Kennedy et al, 2016). The physiological role of APP cleaving enzymes in the mature nervous system is incompletely understood and has to be investigated in more detail This lack of knowledge might have contributed to the failure of the γ-secretase inhibitor LY-450139 (Semagacestat) in clinical trials. Altered cognitive function during long-term γ-secretase inhibition in humans might be associated with the preclinical observation that treatment with LY-450139 causes a persistent reduction in dendritic spine density in mice (Bittner et al, 2009). Pharmacological BACE1 inhibition altered dendritic spine formation but did not disrupt substantially the structural integrity of excitatory synapses

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DISCUSSION