Dierich, Marlen, Hartmann, Stephanie, Dietrich, Nadine, Moeser, Philip, Tziridis, Konstantin, Schilling, Achim, Krauss , Patrick, Brede, Franziska, Hessler, Sabine, Karch, Sandra, Oliver, Dominik, Moser, Tobias, Schultze, Holger, Alzheimer, Christian, Leitner, Michael and Huth, Tobias (2019) β-secretase BACE1 is required for normal cochlear function. The journal of neuroscience. ISSN 1529-2401

Abstract

β-secretase BACE1 is an essential player in the amyloid cascade of Alzheimer´s disease (AD),
making the enzyme a prime therapeutic target. Given its many substrates, however, questions remain regarding the safety of chronic BACE1 suppression in AD. Here, we report that BACE1-/-
mice exhibit significant hearing deficits, as indicated by audiometric tests.
Immunohistochemistry revealed aberrant synaptic organization in the cochlea and
hypomyelination of auditory nerve fibres. To determine whether the auditory system would
be susceptible to chronic pharmacological suppression of BACE1, as envisioned for high AD
risk individuals or early-stage AD patients, we administered the established BACE1 inhibitor
NB-360 for six weeks to wild type mice. The drug efficiently suppressed the enzymatic activity
of the secretase, but did not impair hearing performance and did not produce the characteristic neuropathological abnormalities seen in the cochlea of BACE1-/- mice. These data indicate that the hearing loss of BACE1-/- mice represents a developmental phenotype.

Item Type:	Article
Date Deposited:	26 Oct 2019 00:45
Last Modified:	26 Oct 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38522