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BACE inhibition-dependent repair of Alzheimer´s pathophysiology

Keskin, Aylin and Kekus, Maja and Adelsberger, Helmuth and Neumann, Ulf and Shimshek, Derya and Song, Beomjong and Peng, Tingying and Förstl, Hans and Staufenbiel, Matthias and Nelken, Isreal and Konnerth, Arthur and Busche, Marc Aurel (2017) BACE inhibition-dependent repair of Alzheimer´s pathophysiology. Proceedings of the National Academy of Sciences, 114 (32). pp. 8631-8636. ISSN 0027-84241091-6490

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, already used in human clinical trials, have recently been developed. However, although BACE inhibition can reduce cerebral Aβ levels, it remains unclear whether it can also reverse the observed neural circuit and memory impairments associated with AD. Here we employed in vivo two-photon imaging for an in depth analysis of a mouse model of AD. We demonstrate that in addition to reducing Aβ-burden, the inhibition of BACE activity rescues neuronal hyperactivity, impaired long-range circuit function and memory defects. Our findings provide unambiguous evidence that these AD-related neuronal alterations depend on Aβ and highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-related pathophysiological and cognitive impairments.

Item Type: Article
Date Deposited: 30 Dec 2017 00:45
Last Modified: 30 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/29784

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