BACE inhibition-dependent repair of Alzheimer's pathophysiology

Keskin, Aylin D., Kekus, Maja, Adelsberger, Helmuth, Neumann, Ulf, Shimshek, Derya R., Song, Beomjong, Zott, Benedikt, Peng, Tingying, Förstl, Hans, Staufenbiel, Matthias, Nelken, Israel, Sakmann, Bert, Konnerth, Arthur and Busche, Marc Aurel (2017): BACE inhibition-dependent repair of Alzheimer's pathophysiology. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 32: pp. 8631-8636

Abstract

Amyloid-beta (A beta) is thought to play an essential pathogenic role in Alzheimer's disease (AD). A key enzyme involved in the generation of A beta is the beta-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 A beta 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 A beta 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 A beta, mechanistically linking A beta 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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0027-8424
• Language: English