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BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology

Peters, Finn and Salihoglu, Hazal and Rodriguez, Eva and Herzog, Etienne and Blume, Tanja and Filser, Severin and Dorostkar, Mario and Shimshek, Derya and Brose, Nils and Neumann, Ulf and Herms, Jochen (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathologica, 135 (5). pp. 695-710. ISSN 14320533

Abstract

BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive β-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.

Item Type: Article
Keywords: Alzheimer’s disease BACE1 inhibitor treatment In vivo two-photon microscopy Plaque formation Presynaptic dystrophies β-Amyloid plaque
Date Deposited: 03 Jan 2019 00:45
Last Modified: 03 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/33353

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