1. BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology.
- Author
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Peters F, Salihoglu H, Rodrigues E, Herzog E, Blume T, Filser S, Dorostkar M, Shimshek DR, Brose N, Neumann U, and Herms J
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Brain metabolism, Brain pathology, Disease Models, Animal, Disease Progression, Enzyme Inhibitors pharmacology, Female, Humans, Male, Mice, Transgenic, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 genetics, Presenilin-1 metabolism, Vesicular Glutamate Transport Protein 1 genetics, Vesicular Glutamate Transport Protein 1 metabolism, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Peptides metabolism, Aspartic Acid Endopeptidases antagonists & inhibitors, Brain drug effects, Neuroprotective Agents pharmacology, Peptide Fragments metabolism, Picolinic Acids pharmacology, Thiazines pharmacology
- 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.
- Published
- 2018
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