1. BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology
- Author
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Tanja Blume, Severin Filser, Etienne Herzog, Jochen Herms, Mario M. Dorostkar, Finn Peters, Derya R. Shimshek, Nils Brose, Hazal Salihoglu, Eva Ferreira Rodrigues, Ulf Neumann, Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), InnerEarLab, Dept. of Otolaryngology, and Ludwig-Maximilians-Universität München (LMU)
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_treatment ,Thiazines ,pharmacology [Enzyme Inhibitors] ,Plaque, Amyloid ,Synaptic pathology ,antagonists & inhibitors [Amyloid Precursor Protein Secretases] ,Disease ,APP protein, human ,pathology [Alzheimer Disease] ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,pathology [Brain] ,pharmacology [Thiazines] ,β amyloid ,metabolism [Amyloid beta-Protein Precursor] ,drug therapy [Plaque, Amyloid] ,drug therapy [Alzheimer Disease] ,metabolism [Peptide Fragments] ,Aspartic Acid Endopeptidases ,Plaque formation ,Enzyme Inhibitors ,Cognitive decline ,Picolinic Acids ,ComputingMilieux_MISCELLANEOUS ,media_common ,metabolism [Presenilin-1] ,Brain ,genetics [Presenilin-1] ,antagonists & inhibitors [Aspartic Acid Endopeptidases] ,metabolism [Aspartic Acid Endopeptidases] ,amyloid beta-protein (1-42) ,BACE1 inhibitor treatment ,3. Good health ,Neuroprotective Agents ,genetics [Amyloid beta-Protein Precursor] ,pharmacology [Picolinic Acids] ,Disease Progression ,Presynaptic dystrophies ,drug effects [Brain] ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,genetics [Vesicular Glutamate Transport Protein 1] ,Alzheimer’s disease ,metabolism [Alzheimer Disease] ,Drug ,medicine.medical_specialty ,Bace1 protein, mouse ,media_common.quotation_subject ,Transgene ,metabolism [Amyloid beta-Peptides] ,Mice, Transgenic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,In vivo two-photon microscopy ,Pathology and Forensic Medicine ,PSEN1 protein, human ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,In vivo ,metabolism [Vesicular Glutamate Transport Protein 1] ,mental disorders ,Presenilin-1 ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,ddc:610 ,pathology [Plaque, Amyloid] ,Original Paper ,Amyloid beta-Peptides ,Protease ,pharmacology [Neuroprotective Agents] ,business.industry ,amyloid beta-protein (1-40) ,β-Amyloid plaque ,metabolism [Amyloid Precursor Protein Secretases] ,metabolism [Plaque, Amyloid] ,Peptide Fragments ,Disease Models, Animal ,030104 developmental biology ,metabolism [Brain] ,NB-360 ,Vesicular Glutamate Transport Protein 1 ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,business ,030217 neurology & neurosurgery - 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. Electronic supplementary material The online version of this article (10.1007/s00401-017-1804-9) contains supplementary material, which is available to authorized users.
- Published
- 2018
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