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Keskin, A.D.* ; Kekuš, M.* ; Adelsberger, H.* ; Neumann, U.* ; Shimshek, D.R.* ; Song, B.* ; Zott, B.* ; Peng, T. ; Förstl, H.* ; Staufenbiel, M.* ; Nelken, I.* ; Sakmann, B.* ; Konnerth, A.* ; Busche, M.A.*

BACE inhibition-dependent repair of Alzheimer's pathophysiology.

Proc. Natl. Acad. Sci. U.S.A. 114, 8631-8636 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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 Ca(2+) 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alzheimer’s Disease ; Bace Inhibition ; Amyloid-β ; In Vivo Calcium Imaging ; Neural Circuit Dysfunction; Amyloid Precursor Protein; App Transgenic Mice; In-vivo; Beta-protein; Mouse Model; Neuronal Hyperactivity; Diseased Brain; Deposition; Plaques; Memory
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 114, Issue: 32, Pages: 8631-8636 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503800-001
DOI 10.1073/pnas.1708106114
WOS ID WOS:000407129000069
Scopus ID 85026852046
PubMed ID 28739891
Erfassungsdatum 2017-08-02
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