BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Aylin D. Keskin, Maja Kekuš, Helmuth Adelsberger, Ulf Neumann, Derya R. Shimshek, Beomjong Song, Benedikt Zott, Tingying Peng, Hans Förstl, Matthias Staufenbiel, Israel Nelken, Bert Sakmann*, Arthur Konnerth, Marc Aurel Busche

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

Original languageAmerican English
Pages (from-to)8631-8636
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number32
DOIs
StatePublished - 8 Aug 2017

Bibliographical note

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • BACE inhibition
  • In vivo calcium imaging
  • Neural circuit dysfunction

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