Format

Send to

Choose Destination
Acta Neuropathol. 2018 May;135(5):695-710. doi: 10.1007/s00401-017-1804-9. Epub 2018 Jan 11.

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

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17, 81377, Munich, Germany.
2
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
3
Université Bordeaux, IINS, UMR 5297, 33000, Bordeaux, France.
4
CNRS, IINS, UMR 5297, 33000, Bordeaux, France.
5
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
6
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
7
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
8
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17, 81377, Munich, Germany. jochen.herms@med.uni-muenchen.de.
9
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. jochen.herms@med.uni-muenchen.de.
10
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany. jochen.herms@med.uni-muenchen.de.

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.

KEYWORDS:

Alzheimer’s disease; BACE1 inhibitor treatment; In vivo two-photon microscopy; Plaque formation; Presynaptic dystrophies; β-Amyloid plaque

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center