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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)
Verlagsversion Forschungsdaten DOI
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Band: 114, Heft: 32, Seiten: 8631-8636 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Verlagsort Washington
Begutachtungsstatus Peer reviewed