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

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.

• Authors: Finn Peters, Hazal Salihoglu, Eva Rodrigues, Etienne Herzog, Tanja Blume, Severin Filser, Mario Dorostkar, Derya R Shimshek, Nils Brose, Ulf Neumann, Jochen Herms
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 135 Issue 5 Pg. 695-710 (05 2018) ISSN: 1432-0533 [Electronic] Germany
• PMID: 29327084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Enzyme Inhibitors
• NB-360
• Neuroprotective Agents
• PSEN1 protein, human
• Peptide Fragments
• Picolinic Acids
• Presenilin-1
• Thiazines
• Vesicular Glutamate Transport Protein 1
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, metabolism)
• Brain (drug effects, metabolism, pathology)
• Disease Models, Animal
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Male
• Mice, Transgenic
• Neuroprotective Agents (pharmacology)
• Peptide Fragments (metabolism)
• Picolinic Acids (pharmacology)
• Plaque, Amyloid (drug therapy, metabolism, pathology)
• Presenilin-1 (genetics, metabolism)
• Thiazines (pharmacology)
• Vesicular Glutamate Transport Protein 1 (genetics, metabolism)