TY - JOUR
T1 - BACE inhibition-dependent repair of Alzheimer’s pathophysiology
AU - Keskin, Aylin D.
AU - Kekuš, Maja
AU - Adelsberger, Helmuth
AU - Neumann, Ulf
AU - Shimshek, Derya R.
AU - Song, Beomjong
AU - Zott, Benedikt
AU - Peng, Tingying
AU - Förstl, Hans
AU - Staufenbiel, Matthias
AU - Nelken, Israel
AU - Sakmann, Bert
AU - Konnerth, Arthur
AU - Busche, Marc Aurel
N1 - Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/8/8
Y1 - 2017/8/8
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyloid-β
KW - BACE inhibition
KW - In vivo calcium imaging
KW - Neural circuit dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85026852046&partnerID=8YFLogxK
U2 - 10.1073/pnas.1708106114
DO - 10.1073/pnas.1708106114
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C2 - 28739891
AN - SCOPUS:85026852046
SN - 0027-8424
VL - 114
SP - 8631
EP - 8636
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -
